MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'The Journal of Clinical Pharmacology' source. Fri, 19 Mar 2010 15:14:37 +0100 http://www.medworm.com/index.php?rid=3357130&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20220040%26dopt%3DAbstract Conclusions: After L-DOPS administration plasma, NE levels do not increase sufficiently to increase blood pressure. Pressor responses to L-DOPS seem to reflect NE produced extraneuronally that escapes extensive enzymatic deamination and O-methylation and evokes vasoconstriction before reaching the systemic circulation. PMID: 20220040 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3357130 Wed, 10 Mar 2010 00:00:00 +0100 3357130 http://www.medworm.com/index.php?rid=3357127&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20220041%26dopt%3DAbstract Authors: Bottenberg MM, Hegge KA, Eastman DK, Kumar R PMID: 20220041 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3357127 Wed, 10 Mar 2010 00:00:00 +0100 3357127 http://www.medworm.com/index.php?rid=3357126&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20220042%26dopt%3DAbstract This study investigated the relationship between pharmacokinetics and pharmacodynamics of mycophenolic acid (MPA) in liver transplant patients receiving mycophenolate mofetil (MMF). Total and free plasma MPA concen-trations were determined by high-performance liquid chromatography before MMF dose and at 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 12 hours after dosing in 27 patients. The inhibitory capacity of serum MPA on proliferation of CEM cells was monitored at 0, 1, and 2 hours. The concentration of free MPA at 0, 1, and 2 hours (C0h, C1h, C2h) and the area under the concentration-time curve at 0 to 12 hours (AUC0-12h) of free MPA were significantly related to those of total MPA (P < .05). C1h and C2h of total and free MPA were conversely related with the rate of proliferation of CEM cells (... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3357126 Wed, 10 Mar 2010 00:00:00 +0100 3357126 http://www.medworm.com/index.php?rid=3357125&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20220043%26dopt%3DAbstract This article discusses the elucidation and targeting of novel cellular pathways that are intimately tied to oxidative stress in diabetes mellitus for new treatment strategies. Pathways that involve wingless, beta-nicotinamide adenine dinucleotide (NAD(+)) precursors, and cytokines govern complex biological pathways that determine both cell survival and longevity during diabetes mellitus and its complications. Furthermore, the role of these entities as biomarkers for disease can further enhance their utility irrespective of their treatment potential. Greater understanding of the intricacies of these unique cellular mechanisms will shape future drug discovery for diabetes mellitus to provide focused clinical care with limited or absent long-term complications. PMID: 20220043 [PubMed - as... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3357125 Wed, 10 Mar 2010 00:00:00 +0100 3357125 http://www.medworm.com/index.php?rid=3357124&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20220044%26dopt%3DAbstract In conclusion, CP-642,931 is a potent and specific SDI that is rapidly absorbed through the oral route and effectively inhibits SDH. However, the drug is not well tolerated due to adverse neuromuscular effects. PMID: 20220044 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3357124 Wed, 10 Mar 2010 00:00:00 +0100 3357124 http://www.medworm.com/index.php?rid=3357123&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20220045%26dopt%3DAbstract Authors: Kirby LC, Johnson BM, Adams LM, Eberwein DJ, Zhang K, Murray SC, Lates CD, Blum RA, Morris SR Casopitant, a novel NK-1 receptor antagonist under investigation for the prevention of postoperative and chemotherapy-induced nausea and vomiting, is a weak to moderate inhibitor of CYP3A and a moderate inducer of CYP2C9 in vitro. Furthermore, both CYP enzymes are involved in the metabolism of R- and S-warfarin, respectively. This clinical study was conducted to explore the potential drug-drug interaction between casopitant and warfarin. In total, 97 healthy participants were enrolled and 54 completed the study. Participants received individualized daily dosing of warfarin to an international normalized ratio (INR) of 1.3 to 2.3 over a 14-day period (period 1). Immediately following p... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3357123 Wed, 10 Mar 2010 00:00:00 +0100 3357123 http://www.medworm.com/index.php?rid=3357122&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20220046%26dopt%3DAbstract Authors: Jauslin PM, Frey N, Karlsson MO A model able to simultaneously characterize and simulate 24-hour glucose and insulin profiles following multiple meal tests was developed, extending an integrated glucose-insulin model for oral glucose tolerance tests that was previously published. The analysis was based on glucose and insulin measurements from 59 placebo-treated patients with type 2 diabetes. Circadian variations in glucose homeostasis were assessed on relevant parameters based on literature review. They were best described by a nighttime dip in insulin secretion between approximately 9 p.m. and 5 a.m. using a modulator function. The integrated glucose-insulin model has thus been shown to be applicable to real-life situations determined by multiple meals over the course of a da... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3357122 Wed, 10 Mar 2010 00:00:00 +0100 3357122 http://www.medworm.com/index.php?rid=3338750&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20200268%26dopt%3DAbstract Authors: Hussey EK, Dobbins RL, Stoltz RR, Stockman NL, O'Connor-Semmes RL, Kapur A, Murray SC, Layko D, Nunez DJ Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of the sodium-dependent glucose cotransporter-2 in the renal tubule. The pharmacokinetics and pharmacodynamics of sergliflozin were examined during administration of sergliflozin etabonate (500 or 1000 mg) or placebo 3 times daily (tid) for 14 days in healthy overweight or obese human volunteers (n = 18). At the doses tested, sergliflozin showed less than dose-proportional pharmacokinetic characteristics. Mean half-life of the active entity was approximately 2 hours; there was no evidence of drug accumulation. Sergliflozin etabonate produced rapid and sustained suppression of renal glucose r... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3338750 Wed, 03 Mar 2010 00:00:00 +0100 3338750 http://www.medworm.com/index.php?rid=3338749&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20200269%26dopt%3DAbstract Authors: Knebel W, Rao N, Uchimura T, Mori A, Fisher J, Gastonguay MR, Chaikin P This model-based analysis quantifies the population pharmacokinetics (PK) of orally administered istradefylline, a selective adenosine A2A receptor antagonist, in healthy subjects and patients with Parkinson's disease, including the estimation of covariate effects on istradefylline PK parameters. Istradefylline plasma concentration data from 8 phase 1 and 8 phase 2/3 studies conducted in 1449 patients and normal, healthy volunteers aged from 18 to 87 years were best described by a 2-compartment model with first-order absorption parameterized in terms of apparent oral clearance (CL/F), apparent central volume of distribution (V2/F), apparent intercompartmental clearance (Q/F), apparent peripheral volume of ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3338749 Wed, 03 Mar 2010 00:00:00 +0100 3338749 http://www.medworm.com/index.php?rid=3332030&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20197485%26dopt%3DAbstract Authors: Ishizuka H, Yoshiba S, Yoshihara K, Okabe H This open-label, single-dose study assessed the safety and pharmacokinetics of laninamivir, a new long-acting neuraminidase inhibitor, after an inhaled 20-mg dose of its prodrug, CS-8958, to a total of 20 subjects with normal, mild, moderate, or severe renal impairment. CS-8958 and laninamivir concentrations were measured in plasma and urine by validated liquid chromatography tandem mass spectrometry methods. The area under the concentration- time curve extrapolated to infinity (AUC0-inf), maximum concentration (Cmax), and time to Cmax of CS-8958 did not change with the degree of renal impairment, whereas the half-life (t(1/2)) of CS-8958 increased with increasing renal insufficiency. The AUC0-infand Cmax of laninamivir tended to inc... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3332030 Tue, 02 Mar 2010 00:00:00 +0100 3332030 http://www.medworm.com/index.php?rid=3332029&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20197486%26dopt%3DAbstract Authors: Liu F, Vessey L, Wenning L, Connolly S, Buckland M, Johnson-Levonas AO, Denker A, Wagner JA, Lai E Laropiprant, a prostaglandin D2 receptor-1 antagonist shown to reduce flushing symptoms, has been combined with niacin for treatment of dyslipidemia. This open-label, randomized, 2-period crossover study assessed the effects of laropiprant on the pharmacokinetics of digoxin, with 13 healthy subjects randomized to 2 treatments administered in random order with a 10-day or longer washout period: (A) single-dose digoxin 0.5 mg on day 1 and once-daily oral doses of laropiprant 40 mg for 10 days beginning 5 days prior to digoxin dosing (day -5 to day 5); (B) single-dose digoxin 0.5 mg on day 1. Blood was collected over the course of 120 hours post digoxin dose to assess pharmacokineti... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3332029 Tue, 02 Mar 2010 00:00:00 +0100 3332029 http://www.medworm.com/index.php?rid=3332028&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20197487%26dopt%3DAbstract Authors: Qu HY, Gao HZ, Hao GT, Li YY, Li HY, Hu JC, Wang XF, Liu WL, Liu ZY The compound naphthoquine phosphate is a novel antimalaria drug tablet containing a fixed-dose combination of naphthoquine phosphate and artemisinin in a 1:2.5 ratio. A randomized, open study on the safety and tolerability was conducted in 28 healthy male volunteers using a single oral dose of 350 mg, 700 mg, 1400 mg, or 2100 mg of artemisinin-naphthoquine phosphate. Pharmacokinetics at the last 3 doses were examined in 30 volunteers. Food effects were also determined. Serial blood samples up to 216 hours after single oral dose administration were analyzed for plasma concentrations using a validated high-performance liquid chromatography-tandem mass spectrometry assay. The compound was well tolerated at single... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3332028 Tue, 02 Mar 2010 00:00:00 +0100 3332028 http://www.medworm.com/index.php?rid=3332027&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20197488%26dopt%3DAbstract Authors: Hursitoglu M, Cikrikcioglu MA, Gundogan E, Ozkan O, Cordan I, Yigit Y, Kara O, Soysal P, Apikoglu Rabus S, Celepkolu T, Tukek T PMID: 20197488 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3332027 Tue, 02 Mar 2010 00:00:00 +0100 3332027 http://www.medworm.com/index.php?rid=3332026&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20197489%26dopt%3DAbstract Authors: Yang Z, Rodrigues AD Plasma 4beta-hydroxycholesterol (4betaHC) has been proposed as an endogenous marker of cytochrome P450 3A (CYP3A). To assess its utility as a CYP3A metric, a pharmacokinetic model, assuming no alteration in cholesterol plasma concentrations, was developed to simulate the effect of CYP3A induction and inhibition on 4betaHC plasma levels under different treatment durations. By incorporating the long plasma half-life of 4betaHC (~17 days) into the model, the inductive effect of 2 known inducers (carbamazepine and rifampicin) reported in the literature was adequately described. Furthermore, the simulations showed that it was possible to resolve none, weak, moderate, and potent inducers within 2 weeks of dosing. On the other hand, simulations indicated that at ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3332026 Tue, 02 Mar 2010 00:00:00 +0100 3332026 http://www.medworm.com/index.php?rid=3305633&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20179322%26dopt%3DAbstract This study aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for C.E.R.A., a continuous erythropoietin receptor activator. C.E.R.A. is administered via intravenous (IV) and subcutaneous (SC) routes once every 2 weeks (Q2W) or once every 4 weeks (Q4W), respectively, to correct or maintain hemoglobin levels in chronic kidney disease (CKD) patients. Population models were specified to describe C.E.R.A. (PK) and hemoglobin (PD) concentrations over time, using data from 3 phase III, open-label, randomized, parallel-group, multicenter studies that examined IV or SC C.E.R.A. administration Q2W and Q4W in erythropoiesis-stimulating agent (ESA)-naïve and ESA-treated patients. C.E.R.A. PK was described by a 1-compartment model: drug clearance = 0.75 L/d, volume of dist... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3305633 Tue, 23 Feb 2010 00:00:00 +0100 3305633 http://www.medworm.com/index.php?rid=3298788&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20173082%26dopt%3DAbstract Authors: Han TH, Blanchard RL, Palcza J, McCrea JB, Laethem T, Willson KJ, Xu Y, Ermlich S, Boyle J, Lines C, Gutierrez M, Van Bortel L, Xiao AJ, Sinclair S, Hickey L, Panebianco D, Murphy MG Telcagepant is a novel, orally active, and selective calcitonin gene-related peptide receptor antagonist being developed for acute treatment of migraine with and without aura. Three separate clinical studies were conducted to evaluate the pharmacokinetics and tolerability of telcagepant following single oral doses in healthy young and elderly men and women and multiple oral doses in men. Telcagepant was rapidly absorbed with a time to maximum concentration of approximately 1.5 hours. The terminal half-life was approximately 6 hours. A greater than dose-proportional increase was observed in the are... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3298788 Fri, 19 Feb 2010 00:00:00 +0100 3298788 http://www.medworm.com/index.php?rid=3298787&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20173083%26dopt%3DAbstract In this study, the authors comprehensively assessed the allele frequencies of 165 variants comprising 27 drug-metabolizing enzyme and transporter (DMET) genes from 2188 participants across 3 major ethnic populations: Caucasians, Africans, and East Asians. This sample size was sufficiently large to demonstrate genetic differences among these major ethnic groups while concomitantly confirming similarities among East Asian subpopulations (Korean, Han Chinese, and Japanese). A comprehensive presentation of allele and genotype frequencies is included in the online supplement, and 3 of the most widely studied cytochrome P450 (CYP) genes, CYP2D6, CYP2C19, and CYP2C9; 2 non-CYP enzymes, NAT1 and TMPT; and 2 transporter genes, SLCO1B1 and SLCO2B1, are presented herein according to ethnic classifica... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3298787 Fri, 19 Feb 2010 00:00:00 +0100 3298787 http://www.medworm.com/index.php?rid=3298786&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20173084%26dopt%3DAbstract Authors: Ermer J, Homolka R, Martin P, Buckwalter M, Purkayastha J, Roesch B The pharmacokinetics of lisdexamfetamine dimesylate, a long-acting prodrug stimulant, and its active moiety, d-amphetamine, including dose-proportionality and variability, were assessed in 20 healthy adults. Subjects received a single dose, sequentially, of 50, 100, 150, 200, and 250 mg of lisdexamfetamine dimesylate. Plasma lisdexamfetamine dimesylate and d-amphetamine were measured before dosing and 0.25 to 96 hours postdose. Dose-proportionality and intersubject and intrasubject variability of pharmacokinetic parameters were examined. Safety assessments included adverse events. All 20 subjects received 50 and 100 mg while 18, 12, and 9 subjects received 150, 200, and 250 mg of lisdexamfetamine dimesylate, r... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3298786 Fri, 19 Feb 2010 00:00:00 +0100 3298786 http://www.medworm.com/index.php?rid=3298785&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20173085%26dopt%3DAbstract Authors: Anderson MS, Mabalot Luk JA, Hanley WD, Jin B, Riesenberg RA, Wenning LA, Chodakewitz JA, Wagner JA, Iwamoto M A randomized, placebo-controlled, 2-period crossover study in subjects on methadone maintenance therapy was conducted to assess the effect of the HIV-1 integrase inhibitor, raltegravir, on the pharmacokinetics of methadone. Twelve HIV-negative male and female subjects stabilized on an oral methadone program were enrolled. Subjects maintained their prescribed oral doses of methadone throughout the study and, in each of 2 periods, received either 400 mg of raltegravir or matching placebo every 12 hours on days 1 through 10 of each treatment period with a washout of 7 days between periods. Plasma samples for analysis of methadone pharmacokinetics were collected over 24 h... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3298785 Fri, 19 Feb 2010 00:00:00 +0100 3298785 http://www.medworm.com/index.php?rid=3298784&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20173086%26dopt%3DAbstract Authors: Karhu D, Groenewoud G, Potgieter L, Mould DR An extended-release trazodone HCl formulation, Trazodone Contramid OAD (TzCOAD), was developed as scored 150-mg and 300-mg caplets for once-daily administration. Dose proportionality of intact and bisected caplets (dose range, 75-375 mg) was evaluated in a single-dose, randomized, 5-way crossover study. Plasma trazodone and m-chlorophenylpiperazine (mCPP) levels were determined using a validated liquid chromatography-tandem mass spectroscopy method. Dose proportionality was assessed based on confidence intervals for logarithmically transformed, dose-normalized maximum plasma concentration (Cmax), area under the plasma concentration versus time data pairs (AUC0-t), and area under the curve from time 0 to infinity (AUC0-infinity) in r... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3298784 Fri, 19 Feb 2010 00:00:00 +0100 3298784 http://www.medworm.com/index.php?rid=3298783&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20173087%26dopt%3DAbstract Authors: Cotte E, Colomban O, Guitton J, Tranchand B, Bakrin N, Gilly FN, Glehen O, Tod M The aim of this work was to study the pharmacokinetics of cisplatinum during closed abdominal hyperthermic intraperitoneal chemotherapy (HIPEC) using a population pharmacokinetics approach. Forty patients were treated between January 2003 and December 2004. Peritoneal and blood concentrations of cisplatinum were used to develop a pharmacokinetic model of the peritoneal and plasma compartments using NONMEM software. Different covariables were analyzed to identify those that explain part of the interindividual variability of the pharmacokinetic parameters. Relationships between the area under the concentration-time curve (AUC) and hematological and renal toxicity and efficiency were explored. The ph... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3298783 Fri, 19 Feb 2010 00:00:00 +0100 3298783 http://www.medworm.com/index.php?rid=3298782&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20173088%26dopt%3DAbstract This article discusses the bioequivalence of Omnitrope (Sandoz's rhGH biosimilar) and Genotropin (reference rhGH product), assessed in the first 2 clinical phase 1 studies conducted during the development of Omnitrope. Both of these phase 1 studies were randomized, double-blind, crossover studies, each involving 24 healthy volunteers who underwent pituitary somatrope cell down-regulation using octreotide. Three different formulations of recombinant human growth hormone (rhGH) were compared: Omnitrope lyophilisate, Omnitrope liquid and Genotropin (lyophilized powder for injection). Both pharmacokinetics (area under the curve [AUC], Cmax, tmax and t1/2) and pharmacodynamics (serum levels of insulin-like growth factor 1, insulin-like growth factor binding protein-3 and non-esterified fatty ac... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3298782 Fri, 19 Feb 2010 00:00:00 +0100 3298782 http://www.medworm.com/index.php?rid=3292190&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20160155%26dopt%3DAbstract In conclusion, both CYP3A5*3 and MDR1 variants influenced the extent of CYP3A inhibition by grapefruit juice in Chinese healthy subjects. The genetic variations influencing the CYP3A inhibitive phenotype might be helpful to explain the individual variability of grapefruit juice-drug interactions. PMID: 20160155 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3292190 Tue, 16 Feb 2010 00:00:00 +0100 3292190 http://www.medworm.com/index.php?rid=3292189&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20160156%26dopt%3DAbstract Authors: Cai G, Thiessen JJ, Baidoo CA, Fossler MJ Studies to establish bioequivalence (BE) of a drug are important elements in support of drug applications. A typical BE study is conducted as a single dose, randomized, 2-period crossover design. For drugs with long half lives (>/= 48 hours) and evaluation of multiple BE objectives in 1 trial, this design may not be adequate. A parallel design may then be a more appropriate choice. However, parallel designs require increased sample size, which can become substantial. One option that is a compromise between the complete randomized block design and the parallel design is a partial-block crossover design. This approach came about during the development of a combination of dutasteride and tamsulosin. Previous experience with performing ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3292189 Tue, 16 Feb 2010 00:00:00 +0100 3292189 http://www.medworm.com/index.php?rid=3292188&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20160157%26dopt%3DAbstract Authors: Retlich S, Duval V, Graefe-Mody U, Jaehde U, Staab A The pharmacokinetics of the novel dipeptidyl-peptidase 4 (DPP-4) inhibitor linagliptin is nonlinear. Based on in vitro experiments, concentration-dependent binding to DPP-4 is the most likely cause for the nonlinearity. Population pharmacokinetic/pharmacodynamic modeling was performed using linagliptin plasma concentrations and plasma DPP-4 activities from 2 phase 2a studies. In these studies, type 2 diabetic patients received either 1, 2.5, 5, or 10 mg of linagliptin once daily over 12 days (study 1) or 2.5, 5, or 10 mg of linagliptin once daily over 28 days (study 2). The modeling results supported the hypothesis that linagliptin exhibits target-mediated drug disposition. The linagliptin plasma concentrations were best des... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3292188 Tue, 16 Feb 2010 00:00:00 +0100 3292188 http://www.medworm.com/index.php?rid=3292187&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20160158%26dopt%3DAbstract Authors: Chen N, Lau H, Choudhury S, Wang X, Assaf M, Laskin OL Lenalidomide is a thalidomide analog and an immunomodulatory drug with demonstrated efficacy in various hematological malignancies. The distribution of lenalidomide into semen was evaluated in healthy subjects. Twenty-four male subjects were randomized into 4 equal groups for semen collection. All subjects received lenalidomide 25 mg once daily for 4 days. After the last dose, a single semen sample was collected from subjects, at approximately 2, 24, 72, and 168 hours for groups 1, 2, 3, and 4, respectively, and serial blood sampling was performed for 24 hours in all groups. The mean lenalidomide concentration in semen was 478 ng/mL at 2 hours and 10.0 ng/mL at 24 hours, which was higher than was the corresponding drug con... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3292187 Tue, 16 Feb 2010 00:00:00 +0100 3292187 http://www.medworm.com/index.php?rid=3280610&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20154293%26dopt%3DAbstract Authors: Neely M, Jelliffe R PMID: 20154293 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3280610 Fri, 12 Feb 2010 00:00:00 +0100 3280610 http://www.medworm.com/index.php?rid=3280609&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20154294%26dopt%3DAbstract This article describes how a model-based analysis was used to aid development of a novel formulation technology. Paracetamol (acetaminophen) was used as the motivating example with 4 different formulations (2 developmental and 2 commercial) compared using stochastic (Monte Carlo) pharmacokinetic (PK)-pharmacodynamic (PD) simulations to explore potential differences in pharmacodynamic outcomes. PK models were developed from data collected during an intensively sampled, 4-arm crossover trial in 25 fasted healthy subjects, administered 1 g of paracetamol in 4 different formulations. The PK models were linked to a previously published PD model that quantified pain relief over time following tonsillectomy. The number needed to treat (NNT) was the primary numeric used to compare effectiveness. T... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3280609 Fri, 12 Feb 2010 00:00:00 +0100 3280609 http://www.medworm.com/index.php?rid=3270300&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20150520%26dopt%3DAbstract Authors: Jarugula V, Yeh CM, Howard D, Bush C, Keefe DL, Dole WP Gender and body weight influence the pharmacokinetics and pharmacodynamics of many drugs. This pooled analysis of 17 clinical studies evaluated the effect of gender, body mass index (BMI), body weight, and lean body weight (LBW) on the pharmacokinetics of the direct renin inhibitor aliskiren in healthy volunteers (n = 392). A separate pooled analysis of 5 clinical studies in patients with hypertension (n = 2327) assessed the influence of gender and BMI on the effects of aliskiren on plasma renin activity and blood pressure. Area under the aliskiren plasma concentration-time curve (AUCtau) was 22% lower and the peak aliskiren plasma concentration (Cmax) was 24% lower in men than women (P < .05). BMI was not significantl... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3270300 Thu, 11 Feb 2010 00:00:00 +0100 3270300 http://www.medworm.com/index.php?rid=3270299&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20150521%26dopt%3DAbstract Authors: Vasisht N, Gever LN, Tagarro I, Finn AL Fentanyl buccal soluble film (FBSF) is a rapidly absorbed transmucosal formulation of fentanyl for the management of breakthrough pain in opioid-tolerant patients with cancer. This open-label, 3-period, sequential dose study evaluated the dose-to-dose reproducibility of the pharmacokinetics of fentanyl following the administration of 600- or 1800-microg doses of FBSF in 12 naltrexone-blocked, healthy adult volunteers. Subjects received 3 study treatments: single doses of 600 microg of FBSF on day 1 and day 4 and three 600-microg doses administered at 1-hour intervals on day 7. Plasma fentanyl concentrations were measured over a 48-hour period after each single dose of FBSF and 72 hours after the 3-dose regimen. Peak plasma concentrations... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3270299 Thu, 11 Feb 2010 00:00:00 +0100 3270299 http://www.medworm.com/index.php?rid=3270298&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20150522%26dopt%3DAbstract Authors: Patel CG, Zhang J, Li L, Gooding L, Croop R, Li T, Boulton DW PMID: 20150522 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3270298 Thu, 11 Feb 2010 00:00:00 +0100 3270298 http://www.medworm.com/index.php?rid=3270297&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20150523%26dopt%3DAbstract This study demonstrates the value of monitoring the plasma pharmacokinetics of the inhibitor, and not only the drug under investigation, to improve the mechanistic interpretation. PMID: 20150523 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3270297 Thu, 11 Feb 2010 00:00:00 +0100 3270297 http://www.medworm.com/index.php?rid=3270296&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20150524%26dopt%3DAbstract The objectives of this study were to characterize pharmacokinetics (PK) and pharmacodynamics (PD) of FP and a pharmacologically active metabolite of CIC (desisobutyrylciclesonide [Des-CIC]) using a nonlinear mixed-effects modeling approach, to investigate selected covariate effects on PK and PD parameters of FP and Des-CIC, and to assess the systemic effects of FP and CIC on serum cortisol suppression in patients with persistent asthma. This was a randomized, double-blind, placebo-controlled, double-dummy, 5-period, crossover, multicenter clinical study. A total of 32 patients were enrolled and given basic asthma medication (salmeterol 50 mug twice per day [BID] and CIC 160 mug daily in the evening) through the entire study. During crossover periods, patients were given placebo or CIC 160 ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3270296 Thu, 11 Feb 2010 00:00:00 +0100 3270296 http://www.medworm.com/index.php?rid=3270295&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20150525%26dopt%3DAbstract Authors: Zhang P, Qin L Prolonged prosthetic life span is a goal that orthopedic surgeons are pursuing. Both septic and aseptic loosening may lead to prosthetic failure. For decades, antibiotics have been applied in arthroplasty to prevent septic loosening, with excellent clinical results, although few therapies have been able to prevent aseptic loosening. Research on aseptic loosening indicates that osteoclasts play an essential role in this process. Thus, the exploration of osteoclastogenesis inhibitor has become of interest. Erythromycin is a broad-spectrum antimicrobial that has been used to prevent postoperative infection after artificial joint replacement. A new function to inhibit particle-induced osteolysis has been discovered recently. Fundamental research indicates that eryth... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3270295 Thu, 11 Feb 2010 00:00:00 +0100 3270295 http://www.medworm.com/index.php?rid=3270294&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20150526%26dopt%3DAbstract This study assessed the impact of this interaction on the lipid-lowering effects of simvastatin. Chinese patients with hypercholesterolemia were randomized to receive simvastatin 20 mg daily alone or together with diltiazem 60 mg 3 times daily for 4 weeks with a washout period of 4 weeks in an open-label, crossover study. Blood pressure, fasting serum lipid profile, and safety tests were determined at baseline and after each treatment period. Trough serum diltiazem was measured at the end of the 4-week combination treatment. In the 30 patients who completed the study, simvastatin treatment significantly reduced low-density lipoprotein cholesterol by mean (+/- standard error) 41.0% +/- 2.2% (P < .001), and the combination with diltiazem showed an additional reduction of 1.66% (95% confid... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3270294 Thu, 11 Feb 2010 00:00:00 +0100 3270294 http://www.medworm.com/index.php?rid=3270293&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20150527%26dopt%3DAbstract This article proposes a systematic approach that can be used to assess the relative contributions of ontogeny and genetic variation for a given compound. Application of the strategy is illustrated using the current regulatory dilemma posed by the safety and effectiveness of over-the-counter cough and cold remedies as an example. The results of the analysis can be used to aid in the design of studies to yield maximally informative data in pediatric populations of different ages and developmental stages and thereby improve the efficiency of study design. PMID: 20150527 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3270293 Thu, 11 Feb 2010 00:00:00 +0100 3270293 http://www.medworm.com/index.php?rid=3263878&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20147613%26dopt%3DAbstract Authors: Overton ET, Tschampa JM, Klebert M, Royal M, Rodriguez M, Spitz T, Kim G, Mondy KE, Acosta EP PMID: 20147613 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3263878 Wed, 10 Feb 2010 00:00:00 +0100 3263878 http://www.medworm.com/index.php?rid=3263877&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20147614%26dopt%3DAbstract Authors: McKee J, Bairstow S, Szabo C, Ray J, Wielgos T, Hu P, Chess E, Nordhaus M, Hai T, Campbell J, Donovan S, Riedel N, Cammack J, Johnson R, Viseux N From late December 2007 to February 2008, the number of adverse responses to heparin infusions rose noticeably above baseline levels in North America, ultimately resulting in a widespread recall of all heparin vial products made by Baxter Healthcare. Using various analytical techniques and the de novo synthesis of a fully sulfated chondroitin sulfate (FSCS) derivative, the authors have confirmed the identity of the contaminant as an oversulfated chondroitin sulfate (OSCS) and have also defined the heterogeneity and concentration of this contaminant in various lots of heparin. Using both contaminated heparin products and the synthetic... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3263877 Wed, 10 Feb 2010 00:00:00 +0100 3263877 http://www.medworm.com/index.php?rid=3263876&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20147615%26dopt%3DAbstract The objective was to develop a population pharmacokinetic-pharmacogenetic model of mycophenolic acid following administration of mycophenolate mofetil (MMF) in de novo pediatric renal-transplant patients and identify factors that explain variability. The pharmacokinetic samples were collected from 89 de novo pediatric renal-transplant patients treated with MMF and studied during the first 60 postoperative days. All patients were genotyped for UGT1A8-A9, UGT2B7, and ABCC2. Population pharmacokinetic analysis was performed with the NONMEM and was validated using bootstrap visual predictive check. The pharmacokinetic data were best described by a 2-compartment model with Erlang distribution to describe the absorption phase. The covariate analysis identified body weight as an individual factor... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3263876 Wed, 10 Feb 2010 00:00:00 +0100 3263876 http://www.medworm.com/index.php?rid=3263875&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20147616%26dopt%3DAbstract Authors: Hale G, Rebello P, Al-Bakir I, Bolam E, Wiczling P, Jusko WJ, Vandemeulebroucke E, Keymeulen B, Mathieu C, Ziegler AG, Chatenoud L, Waldmann H Otelixizumab is a chimeric CD3 antibody that has been genetically engineered to remove the glycosylation site in the Fc domain. This limits its ability to bind to complement or Fc receptors and reduces the risk of adverse clinical reactions due to cytokine release. In a trial for treatment of type 1 diabetes, a short treatment with otelixizumab resulted in a reduced requirement for insulin lasting at least 18 months. In the course of this trial, the blood concentrations of the antibody were measured by flow cytometry to determine its pharmacokinetic profile. Dose-dependent accumulation of otelixizumab was demonstrated and modeling of th... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3263875 Wed, 10 Feb 2010 00:00:00 +0100 3263875 http://www.medworm.com/index.php?rid=3263874&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20147617%26dopt%3DAbstract Authors: Wada R, Rohatagi S, Small D, Winters KJ, Salazar DE Inhibition of platelet aggregation (IPA) has been a drug development target in acute coronary syndrome (ACS) for almost 2 decades. The relationship between IPA and cardiovascular (CV) events has not been quantified. Cardiovascular (non fatal myocardial infarction, death) and major bleeding events were extracted from phase 2 or 3 randomized, double-blind trials that evaluated oral and intravenous glycoprotein 2b/3a (GP2b/3a) antagonists and thienopyridines. IPA was extracted from different sources that studied a similar regimen in a similar population. Events were correlated to IPA using a linear relative-risk mixed-effects model. Covariates included type of drug, mean age, gender percentage, and ADP. Clinical trial simulation... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3263874 Wed, 10 Feb 2010 00:00:00 +0100 3263874 http://www.medworm.com/index.php?rid=3263873&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20147618%26dopt%3DAbstract Authors: Bockbrader HN, Radulovic LL, Posvar EL, Strand JC, Alvey CW, Busch JA, Randinitis EJ, Corrigan BW, Haig GM, Boyd RA, Wesche DL Pregabalin has shown clinical efficacy for treatment of neuropathic pain syndromes, partial seizures, and anxiety disorders. Five studies in healthy volunteers are performed to investigate single-and multiple-dose pharmacokinetics of pregabalin. Pregabalin is rapidly absorbed following oral administration, with peak plasma concentrations occurring between 0.7 and 1.3 hours. Pregabalin oral bioavailability is approximately 90% and is independent of dose and frequency of administration. Food reduces the rate of pregabalin absorption, resulting in lower and delayed maximum plasma concentrations, yet the extent of drug absorption is unaffected, suggesting ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3263873 Wed, 10 Feb 2010 00:00:00 +0100 3263873 http://www.medworm.com/index.php?rid=3263884&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20145258%26dopt%3DAbstract This study aimed at characterizing the variation of free MPA exposure with respect to time since transplantation. Three groups (A, B, C) were compared. The median posttransplantation time was 12 days (A, n = 26 pharmacokinetic sessions), 36 days (B, n = 25), and 867 days (C, n = 21). The median MPA AUC0-12 in group A (26.8 mg.h/L) was significantly lower than in groups B (45.2 mg.h/L, P = .031) and C (43.5 mg.h/L, P = .004). Free MPA AUC0-12 was comparable whatever the time (0.41, 0.34, and 0.33 mg.h/L, respectively). MPA apparent clearance (CL/F) was significantly correlated with MPA free fraction (r = 0.60, P < .0001) and approximately 1.7-fold higher in group A compared to groups B and C (P < .05). Enhanced CL/F in relation with an increase in MPA free fraction results in a low AU... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3263884 Tue, 09 Feb 2010 00:00:00 +0100 3263884 http://www.medworm.com/index.php?rid=3263883&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20145259%26dopt%3DAbstract Authors: Ishizuka H, Yoshiba S, Okabe H, Yoshihara K Phase 1 studies of laninamivir, a novel long-acting neuraminidase inhibitor, were carried out to assess its safety, tolerability, and pharmacokinetics after inhaled administration of its prodrug, CS-8958. Healthy male volunteers (total N = 76) participated in double-blind, randomized, placebo-controlled trials and received 5, 10, 20, 40, 80, or 120 mg of a single dose or 20 or 40 mg of a twice-daily dose for 3 days. The clinical and laboratory parameters and plasma and urinary concentrations of CS-8958 and laninamivir for 144 hours post dosing were measured. There were no adverse events related to the test drug. CS-8958 disappeared from plasma with a half-life of about 2 hours, although laninamivir was slowly eliminated from the body... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3263883 Tue, 09 Feb 2010 00:00:00 +0100 3263883 http://www.medworm.com/index.php?rid=3263882&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20145260%26dopt%3DAbstract Authors: Mason JW, Florian JA, Garnett CE, Moon TE, Selness DS, Spaulding RR Moxifloxacin is used in thorough QT studies to assess sensitivity for detection of an increase in QTc. Moxifloxacin is usually over-encapsulated for blinding. However, there is concern that over-encapsulation alters its pharmacokinetics. In a 4-arm, randomized crossover study, 22 volunteers received over-encapsulated moxifloxacin, over-encapsulated placebo, bare moxifloxacin, and intravenous (IV) moxifloxacin. Placebo capsules and IV infusions were administered so that treatments in each arm, except for bare moxifloxacin, were indistinguishable. Pharmacokinetics of the oral treatments were found to be nearly identical and to meet Food and Drug Administration criteria for bioequivalency. Relative to the IV infu... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3263882 Tue, 09 Feb 2010 00:00:00 +0100 3263882 http://www.medworm.com/index.php?rid=3263881&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20145261%26dopt%3DAbstract In conclusion, fenofibric acid is well absorbed throughout the GI tract and has greater bioavailability than fenofibrate in all GI regions. PMID: 20145261 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3263881 Tue, 09 Feb 2010 00:00:00 +0100 3263881 http://www.medworm.com/index.php?rid=3263880&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20145262%26dopt%3DAbstract Authors: Lu J, Poppitt SD, Othman AA, Sunderland T, Ruggiero K, Willet MS, Diamond LE, Garcia WD, Roesch BG, Cooper GJ The selective Cu(II)-chelator, triethylenetetramine (TETA), is undergoing clinical trials for the treatment of heart failure in patients with diabetes. Recently, the authors showed that 2 acetylated metabolites, N1-acetyltriethylenetetramine (MAT) and N1,N10-diacetyltriethylenetetramine (DAT), are formed in humans following oral TETA administration. Thus, it became necessary to determine whether the N-acetyltransferase (NAT) 2 phenotype has any effects on the pharmacological properties and safety profile of TETA. Twelve fast and 12 slow NAT2-phenotype healthy participants were recruited. After oral drug administration, the authors collected plasma and urine samples, me... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3263880 Tue, 09 Feb 2010 00:00:00 +0100 3263880 http://www.medworm.com/index.php?rid=3263879&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20145263%26dopt%3DAbstract The objectives were to evaluate the time course for atenolol pharmacokinetics in lactating women postpartum and to quantify atenolol plasma concentrations in the women's 3-to 4-month-old nursing infants. Data were collected during 1 dosing interval from lactating women treated with atenolol for therapeutic reasons, at 2 to 4 weeks (n = 32), 3 to 4 months (n = 22), and 6 to 8 months (n = 17) postpartum. A single blood sample was collected from 15 nursing infants (3-4 months of age) of the mothers participating in the study. At 2 to 4 weeks, 3 to 4 months, and 6 to 8 months postpartum, atenolol infant doses, relative to the mother's weight-adjusted dose, were 14.6% +/- 7.6%, 8.3% +/- 5.2% and 5.9% +/- 2.9%, respectively. Over this time, maternal atenolol pharmacokinetics did not change to a ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3263879 Tue, 09 Feb 2010 00:00:00 +0100 3263879 http://www.medworm.com/index.php?rid=3247318&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20133507%26dopt%3DAbstract Authors: Watson E, Jonker DM, Jacobsen LV, Ingwersen SH The once-daily human glucagon-like peptide-1 (GLP-1) analog, liraglutide, was recently shown to provide improved glycemic control in subjects with type 2 diabetes (T2D) compared with exenatide. The aim of this work is to estimate the population pharmacokinetics of liraglutide and make a comparison to the pharmacokinetic profile of exenatide. Pharmacokinetic data from 5 published studies of subcutaneous and intravenous administration of liraglutide to healthy volunteers (HV) and subjects with T2D were used to develop a population pharmacokinetic model in NONMEM. Exenatide data came from a published study in T2D. Liraglutide pharmacokinetics were adequately described using a 1-compartment model with sequential zero-and first-order a... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3247318 Thu, 04 Feb 2010 00:00:00 +0100 3247318 http://www.medworm.com/index.php?rid=3247317&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20133508%26dopt%3DAbstract Authors: Ling J, Lyn S, Xu Z, Achira M, Bouman-Thio E, Shishido A, Ford J, Shankar G, Wagner C, Kim KT, Davis HM, Zhou H This phase 1 study evaluated the single-dose pharmacokinetics and safety of subcutaneous golimumab, a human anti-tumor necrosis factor-alpha monoclonal antibody, in healthy Japanese and Caucasian subjects. Eligible subjects were males, aged 20 to 45 years, weighing 50 to 90 kg with a body mass index of 19 to 30 kg/m(2). Japanese and Caucasian subjects were matched by body weight and dose group. Blood samples were collected through day 50 following a single subcutaneous injection of golimumab 50 or 100 mg. The pharmacokinetic parameters were determined using a noncompartmental method. All 51 subjects (24 Japanese, 27 Caucasian) were included in the safety analysis; 47... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3247317 Thu, 04 Feb 2010 00:00:00 +0100 3247317 http://www.medworm.com/index.php?rid=3247316&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20133509%26dopt%3DAbstract This study evaluated the effect of CYP2D6, CYP3A4, and CYP3A5 polymorphisms on dextropropoxyphene disposition in healthy subjects. A total of 14 healthy male Chinese subjects received a single oral dose of a combination tablet of 325 mg of paracetamol and 32.5 mg of dextropropoxyphene. Serial blood samples were collected for up to 24 hours to determine plasma concentrations of paracetamol, dextropropoxyphene, and nordextropropoxyphene by liquid chromatography-tandem mass spectroscopy. CYP2D6, CYP3A4, and CYP3A5 genotyping were performed using polymerase chain reaction-based methods. No CYP3A4 mutant alleles were detected in the study subjects. There were no significant differences (P > .05) in dextropropoxyphene and nordextropropoxyphene pharmacokinetics among CYP2D6 genotypes. In contr... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3247316 Thu, 04 Feb 2010 00:00:00 +0100 3247316 http://www.medworm.com/index.php?rid=3247315&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20133510%26dopt%3DAbstract This study assessed the efficacy and safety of ketoprofen patch compared with placebo in patients who had rheumatoid arthritis and persistent wrist pain. Patients (N = 676) who had achieved systemic disease control with a disease-modifying antirheumatic drug and/or systemic corticosteroid, but still had persistent wrist pain, were randomized to a 2-week course of once-daily treatment with application of a 20-mg ketoprofen patch or a placebo patch to the wrist. The primary efficacy end point was the percent change from baseline to the end of treatment in the intensity of wrist pain scored by each patient on a 100-mm visual analog scale. The mean +/- SD percent change on the pain intensity scale was significantly larger in patients treated with ketoprofen than in those receiving placebo (31.... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3247315 Thu, 04 Feb 2010 00:00:00 +0100 3247315 http://www.medworm.com/index.php?rid=3247314&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20133511%26dopt%3DAbstract In conclusion, because the GMR and 90% CI are within the equivalence interval of 0.8 to 1.25, co-administration of oral treprostinil and bosentan did not result in a pharmacokinetic interaction for either agent. PMID: 20133511 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3247314 Thu, 04 Feb 2010 00:00:00 +0100 3247314 http://www.medworm.com/index.php?rid=3240212&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20124517%26dopt%3DAbstract Authors: Johnson BM, Adams LM, Zhang K, Gainer SD, Kirby LC, Blum RA, Apseloff G, Morrison RA, Schutz RA, Lebowitz PF Casopitant, an antiemetic, is a neurokinin-1 receptor antagonist metabolized primarily by cytochrome P450 3A4 (CYP3A4). Three phase 1 studies with 131 healthy subjects examined the impact of a strong CYP3A inhibitor (ketoconazole) and inducer (rifampin) on the pharmacokinetics and safety of casopitant. Oral casopitant was administered alone (study 1, 100-mg single dose; study 2, 150 mg on day 1, 50 mg on days 2 and 3; study 3, 150-mg single dose) with either 400 mg daily of oral ketoconazole or 600 mg daily of oral rifampin. Ketoconazole increased the maximum observed plasma concentration (Cmax) and area under the plasma concentration time curve to the last sampling tim... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3240212 Tue, 02 Feb 2010 00:00:00 +0100 3240212 http://www.medworm.com/index.php?rid=3240211&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20124518%26dopt%3DAbstract Authors: Morell J, Sullivan B, Khalabuda M, McBride BF Interpatient variability in the safety and efficacy of oral anticoagulation with warfarin presents several challenges to clinicians, thus underscoring the emergent need for new orally available anticoagulants with predictable pharmacokinetic and pharmacodynamic profiles and ability to target circulating clotting factors. Seven compounds including rivaroxaban, apixaban, betrixaban, and eribaxaban are orally available direct inhibitors of activated factor X currently in development for the prevention and treatment of venous thromboembolism and for thromboprophylaxis in patients with atrial fibrillation or following an acute coronary syndrome. At doses used in phase 2 and 3 clinical trials, rivaroxaban and apixaban demonstrated a pred... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3240211 Tue, 02 Feb 2010 00:00:00 +0100 3240211 http://www.medworm.com/index.php?rid=3221413&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20107201%26dopt%3DAbstract In conclusion, by accounting for the effects of developmental factors (body weight), time after transplantation, and cyclosporine dosing frequency/formulation, it may be possible to improve individualization of cyclosporine dosing in children. PMID: 20107201 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3221413 Wed, 27 Jan 2010 00:00:00 +0100 3221413 http://www.medworm.com/index.php?rid=3221412&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20107202%26dopt%3DAbstract In conclusion, single doses of LRPT 50 mg and 600 mg do not prolong the QTcF interval relative to placebo and are generally well tolerated. PMID: 20107202 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3221412 Wed, 27 Jan 2010 00:00:00 +0100 3221412 http://www.medworm.com/index.php?rid=3214286&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20103693%26dopt%3DAbstract Authors: Joy MS, Frye RF, Stubbert K, Brouwer KR, Falk RJ, Kharasch ED There are limited data describing the influence of chronic kidney diseases on the cytochrome P450 2B6 pathway. The purpose of this study was to evaluate the pharmacokinetics of enantiomeric bupropion and hydroxybupropion in patients with glomerulonephritis. Ten patients with biopsy-confirmed lupus nephritis or antineutrophil-associated vasculitis were enrolled for CYP2B6 phenotyping with oral bupropion. Blood and urine were collected over 72 hours for pharmacokinetic analysis. R- and S-bupropion and (R,R) and (S,S) hydroxybupropion were analyzed by high-performance liquid chromatography tandem mass spectrometry. Statistics included paired t tests or nonparametric equivalent. Bupropion (2329 +/- 953 mug*h/L vs 1240 +... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3214286 Tue, 26 Jan 2010 00:00:00 +0100 3214286 http://www.medworm.com/index.php?rid=3214280&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20103694%26dopt%3DAbstract Authors: Periclou A, Palmer RH, Zheng H, Lindamood C Milnacipran is approved for management of fibromyalgia in the United States. In this double-blind, placebo-and active drug-controlled study (N = 100), effects of supratherapeutic doses of milnacipran on cardiac repolarization were evaluated in healthy volunteers. The primary outcome was the largest mean difference between milnacipran and placebo in time-matched baseline-adjusted QT interval corrected for heart rate using an individual correction formula (QTcNi). In addition, data were analyzed using the Fridericia formula (QTcF) and a post hoc piecewise QTcNi analysis based on a dichotomous cut of RR interval data at 800 ms. Moxifloxacin (400 mg single dose) was used to establish assay sensitivity. Using the QTcNi method, the largest... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3214280 Tue, 26 Jan 2010 00:00:00 +0100 3214280 http://www.medworm.com/index.php?rid=3214291&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20100913%26dopt%3DAbstract This study evaluated the potential pharmacokinetic interaction of pamapimod, a p38 mitogen-activated protein kinase inhibitor, and methotrexate (MTX) when administered concomitantly in patients with rheumatoid arthritis (RA); the study also evaluated the pharmacodynamic effects of pamapimod. Twenty-two RA patients on a stable regimen of MTX (10-25 mg/wk; administered on days 1 and 8) were randomized to receive 300 mg of pamapimod (n = 17) or placebo (n = 5) once daily (qd) for 10 days (days 5-14). Blood and urine samples were collected pre-and postdose on days 1 (MTX alone), 7 (pamapimod alone), and 8 (MTX and pamapimod coadministered). No clinically significant changes were observed in plasma exposures and renal clearance of pamapimod, MTX, or their metabolites, whether administered separ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3214291 Mon, 25 Jan 2010 00:00:00 +0100 3214291 http://www.medworm.com/index.php?rid=3208756&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20097931%26dopt%3DAbstract Authors: Frey N, Grange S, Woodworth T Tocilizumab is a humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody that has demonstrated efficacy in the treatment of rheumatoid arthritis (RA). A population pharmacokinetic (PK) model was developed using nonlinear mixed effect modeling to describe the PK profile of tocilizumab and used to estimate interindividual variability and assess the influence of covariates on PK parameters. The model was constructed based on data collected from 1793 patients with moderate to severe RA who received tocilizumab (4 or 8 mg/kg), via intravenous infusion every 4 weeks, during 4 phase III clinical trials. Serum concentration-time profiles of tocilizumab were adequately described by a 2-compartment disposition model with parallel linear and nonline... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3208756 Sat, 23 Jan 2010 00:00:00 +0100 3208756 http://www.medworm.com/index.php?rid=3208755&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20097932%26dopt%3DAbstract Authors: Van Nimmen NF, Poels KL, Menten JJ, Godderis L, Veulemans HA Delivery rates and plasma concentrations vary among patients treated with fentanyl patches. Absorption and urinary excretion characteristics of fentanyl were studied in patients undergoing palliative care. Almost 500 patches were analyzed for residual fentanyl content. Fentanyl and norfentanyl levels were determined in the urine of 50 patients. General and mixed effects linear regression models were established for the relationship between fentanyl dose rate and urinary excretion and to incorporate influencing factors. For different patch nominal dose strengths, wide but comparable variability in estimated dose rate and delivery efficiency was observed (coefficients of variation of 15% to 17%). Fentanyl delivery effi... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3208755 Sat, 23 Jan 2010 00:00:00 +0100 3208755 http://www.medworm.com/index.php?rid=3208754&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20097933%26dopt%3DAbstract Authors: Thyssen A, Rusch S, Herben V, Quiroz J, Mannaert E Long-acting injectable (LAI) risperidone for intramuscular injection into the gluteal muscle every 2 weeks is approved for schizophrenia. The deltoid muscle provides a more accessible injection site and could therefore facilitate patient acceptance of an injectable medication. Two studies in chronic schizophrenic subjects evaluated the pharmacokinetics and tolerability of LAI risperidone administered into the deltoid muscle. The pharmacokinetics following deltoid injection and bioequivalence between deltoid and gluteal administration were assessed in an open-label, single-dose, crossover, fully powered bioavailability study. Tolerability and safety of deltoid LAI risperidone were investigated in an open-label multiple-dose stu... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3208754 Sat, 23 Jan 2010 00:00:00 +0100 3208754 http://www.medworm.com/index.php?rid=3208753&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20097934%26dopt%3DAbstract Authors: Thyssen A, Sharma O, Tianmei S, Aquilina JW, Vandebosch A, Wang SS, Mudumbi R, Hsiao HL Dapoxetine is a short-acting selective serotonin reuptake inhibitor developed for the on-demand treatment of premature ejaculation and is approved in some European Union countries, as well as Mexico and Korea, for this indication. The pharmacokinetics of dapoxetine 30 mg and 60 mg in healthy Chinese (single dose), Japanese, and Caucasian men (single and multiple dose) were assessed in 2 studies. In the 3 ethnic groups, dapoxetine was rapidly absorbed following oral administration, with peak plasma concentrations evident approximately 1 hour after dosing, independent of dose, dosing frequency (single or multiple dosing), or ethnicity. Dapoxetine was eliminated in a biphasic manner with an ap... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3208753 Sat, 23 Jan 2010 00:00:00 +0100 3208753 http://www.medworm.com/index.php?rid=3208752&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20097935%26dopt%3DAbstract Authors: Karara AH, Edeki T, McLeod J, Tonelli AH, Wagner JA The FDA guidance on exploratory IND studies is intended to enable sponsors to move ahead more efficiently with the development of promising candidates. A survey of PhRMA member companies was conducted in 2007 to obtain a cross-sectional industry perspective on the current and future utility of exploratory IND studies. About 56% of survey responders (9 companies of 16 survey responders) conducted or were planning to conduct clinical studies under exploratory INDs. The majority of microdosing studies are performed to characterize human pharmacokinetics or to examine target organ pharmacokinetics using PET imaging techniques. On the other hand, the majority of pharmacological end point studies conducted under exploratory IND are... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3208752 Sat, 23 Jan 2010 00:00:00 +0100 3208752 http://www.medworm.com/index.php?rid=3208751&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20097936%26dopt%3DAbstract Authors: Rhee MS, Hellinger JA, Sheble-Hall S, Cohen CJ, Greenblatt DJ The relationship between plasma protease inhibitor (PI) trough concentrations and hyperlipidemic effects were evaluated retrospectively using data from 2 pilot clinical trials of a double-boosted PI regimen (saquinavir/lopinavir/ritonavir) in 25 HIV patients. The patients' median age was 39 years (range, 25-60). At baseline, PI-naive patients had a median viral load of 53 500 copies/mL and median CD4 of 296 cells/mm(3), while PI-experienced patients had 37 750 copies/mL and 214 cells/mm(3). Plasma PI trough concentrations of saquinavir, lopinavir, and ritonavir at week 12 were 520, 4482, and 153 ng/mL, respectively. At week 12, median fasting lipids increased significantly from baseline: total cholesterol increased ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3208751 Sat, 23 Jan 2010 00:00:00 +0100 3208751 http://www.medworm.com/index.php?rid=3208750&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20097937%26dopt%3DAbstract Authors: Marubashi S, Nagano H, Kobayashi S, Eguchi H, Takeda Y, Tanemura M, Umeshita K, Monden M, Doki Y, Mori M Therapeutic drug monitoring is necessary when using tacrolimus (FK) due to the associated side effects. The aim of this study was to compare the chemiluminescent assay (CMIA) system with the previously established Abbott IMx Tacrolimus II microparticle enzyme immunoassay (MEIA) in liver transplant recipients and evaluate its accuracy. Between March and June 2008, all blood samples from the liver transplant recipients at the hospital were tested for FK trough level using 2 different methods, CMIA and MEIA. The posttransplant time, hematocrit, and other clinical parameters during the study period were recorded. FK trough level was analyzed in 398 samples from 57 liver transpl... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3208750 Sat, 23 Jan 2010 00:00:00 +0100 3208750 http://www.medworm.com/index.php?rid=3198208&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20089825%26dopt%3DAbstract This study prospectively assessed outcomes in a group of patients who were randomly switched from Clozaril to generic clozapine (Gen-Clozapine). The authors examined data from rating scales administered before the switch and at points after the switch. There were no statistically significant differences between the groups on any baseline measures, including psychiatric status and dose of medication. In the group of patients who were switched to the generic formulation, there was a significant increase in Global Assessment Scale scores by the end of the 6-month monitoring period. In the group of patients who remained on Clozaril, a significant decrease in the 32-item Behavior and Symptom Identification Scale scores was found at the end of the monitoring period. The results of this study sug... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3198208 Wed, 20 Jan 2010 00:00:00 +0100 3198208 http://www.medworm.com/index.php?rid=3198207&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20089826%26dopt%3DAbstract Authors: Lippmann M, Karnwal A, Julka IS PMID: 20089826 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3198207 Wed, 20 Jan 2010 00:00:00 +0100 3198207 http://www.medworm.com/index.php?rid=3198206&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20089827%26dopt%3DAbstract This study investigates the potential pharmacokinetic interactions between an antimicrobial agent, moxifloxacin, and 2 immunosuppressant drugs, cyclosporine and tacrolimus, in kidney transplant recipients. Twenty-two kidney transplant patients needing antibiotic therapy for urinary tract infections are enrolled. Eleven patients are under cyclosporine treatment and the other 11 patients are under tacrolimus treatment. Because the urinary tract infections are caused by gram-negative aerobes sensitive to moxifloxacin, this antibiotic is administered by oral route at a dose of 400 mg/d for 1 week; in each patient pharmacokinetic studies are carried out before and at the seventh day of therapy. For both immunosuppressors, none of the pharmacokinetic parameters investigated show statistically si... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3198206 Wed, 20 Jan 2010 00:00:00 +0100 3198206 http://www.medworm.com/index.php?rid=3198205&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20089828%26dopt%3DAbstract Authors: Fuhr U PMID: 20089828 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3198205 Wed, 20 Jan 2010 00:00:00 +0100 3198205 http://www.medworm.com/index.php?rid=3189925&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20081227%26dopt%3DAbstract Authors: Jennings DL, Kalus JS The purpose of this study is to evaluate the effect of adding cilostazol to dual antiplatelet therapy (aspirin and thienopyridine) on rates of restenosis after coronary artery stenting. A meta-analysis is conducted of randomized, controlled trials comparing 3 drug regimens (cilostazol, thienopyridine, aspirin [triple therapy]) with dual anti-platelet therapy to reduce restenosis after coronary stenting. A total of 5 studies are included for analysis. The analysis reveals that triple therapy is used in 796 patients, whereas dual therapy is used in 801 patients. Approximately 56% of patients receive a drug-eluting stent. The 6-month restenosis rates are significantly lower with triple versus dual antiplatelet therapy (12.7% vs 21.9%; odds ratio 0.5; 95% con... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3189925 Sat, 16 Jan 2010 00:00:00 +0100 3189925 http://www.medworm.com/index.php?rid=3189928&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20081063%26dopt%3DAbstract Authors: Borges S, Desta Z, Jin Y, Faouzi A, Robarge JD, Philip S, Nguyen A, Stearns V, Hayes D, Rae JM, Skaar TC, Flockhart DA, Li L Accurate assessment of CYP2D6 phenotypes from genotype is inadequate in patients taking CYP2D6 substrate together with CYP2D6 inhibitors. A novel CYP2D6 scoring system is proposed that incorporates the impact of concomitant medications with the genotype in calculating the CYP2D6 activity score. Training (n = 159) and validation (n = 81) data sets were obtained from a prospective cohort tamoxifen pharmacogenetics registry. Two inhibitor factors were defined: 1 genotype independent and 1 genotype based. Three CYP2D6 gene scoring systems, and their combination with the inhibitor factors, were compared. These 3 scores were based on Zineh, Zanger, and Gaedigk... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3189928 Fri, 15 Jan 2010 00:00:00 +0100 3189928 http://www.medworm.com/index.php?rid=3189927&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20081064%26dopt%3DAbstract The objective of this study was to assess whether simultaneous initiation of warfarin and amiodarone results in early alteration of the international normalized ratio (INR) response to warfarin. Patients initiated on warfarin and amiodarone during the same hospitalization were included in the amiodarone (AMIO) group. Patients initiated on warfarin alone (n = 42) were identified for the CONTROL group. The AMIO and CONTROL groups were matched based on age, gender, and ejection fraction <40% using propensity score matching (final n = 18 patients per group). Total and average daily warfarin dose was lower in the AMIO group, yet INR values were similar on each day between the 2 groups. More patients in the AMIO group had an INR greater than 2 during the 5-day observation period as compared t... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3189927 Fri, 15 Jan 2010 00:00:00 +0100 3189927 http://www.medworm.com/index.php?rid=3189926&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20081065%26dopt%3DAbstract Authors: Ogata K, Mendell-Harary J, Tachibana M, Matsumoto H, Oguma T, Kojima M, Kunitada S This is a clinical safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) study of a single ascending dose (SAD) and a multiple ascending dose (MAD) of the oral direct factor Xa inhibitor edoxaban in healthy males. The placebo-controlled, single-blind, randomized, 2-part study consists of a SAD arm with 85 subjects (10, 30, 60, 90, 120, 150 mg) and a MAD arm with 36 subjects (90 mg daily, 60 mg twice daily, 120 mg daily). Effects of food and formulation (tablet vs solution) are assessed in a crossover substudy. In the SAD, doses are well tolerated up to 150 mg. Exposure is proportional to dose. PK profiles are consistent across dose with rapid absorption, biphasic elimination, an... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3189926 Fri, 15 Jan 2010 00:00:00 +0100 3189926 http://www.medworm.com/index.php?rid=3179538&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20075184%26dopt%3DAbstract This study was carried out to compare the efficacy of intravenous sodium valproate with intramuscular haloperidol in patients with acute mania. A total of 30 patients meeting DSM-IV criteria for acute manic episodes were enrolled. They were randomly assigned to 2 groups of 15 patients each. Both groups were treated twice daily with haloperidol (10 mg, intramuscular) and sodium valproate (500 mg, intravenous). The patients were assessed on days 1, 5, 9, and 13. Improvement in symptoms was assessed by reduction in the Young Mania Rating Scale (YMRS). Outcome criterions for analysis were latency of response and remission; additional drugs were required for sedation. At the end of the 2-week study period, overall response rate in both the groups was similar (P> .1). In comparison to haloper... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3179538 Thu, 14 Jan 2010 00:00:00 +0100 3179538 http://www.medworm.com/index.php?rid=3179537&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20075185%26dopt%3DAbstract Authors: Salinger DH, Vicini P, Blough DK, O'Donnell PV, Pawlikowski MA, McCune JS Therapeutic drug monitoring of daily intravenous (IV) busulfan currently requires hospital admission. Population pharmacokinetic modeling and determination of an optimal pharmacokinetic sampling schedule over 6 hours could allow for personalizing these busulfan doses in the outpatient clinic. A retrospective evaluation of daily IV busulfan pharmacokinetics was conducted in 37 adults. SPK and NONMEM software were used to estimate the population pharmacokinetic parameters. Subsequent to model building, the area under the concentration-time curve (AUC) was computed using NONMEM. A 1-compartment model best fit the data. The optimal 6-hour outpatient sampling schedule was constructed using a simulation approa... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3179537 Thu, 14 Jan 2010 00:00:00 +0100 3179537 http://www.medworm.com/index.php?rid=3173298&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20067942%26dopt%3DAbstract Authors: Pelham R, Alcorn H, Cleveland MV The pharmacokinetics (PK) of an oral sulfate solution (OSS) for bowel cleansing preparation was studied. OSS (30 g of sulfate) was split between 2 doses, 12 hours apart. Safety measures included electrocardiography, vital signs, adverse events, hematology, blood chemistry, and urinalysis. Six adult patients with moderate renal disease (MRD), 6 with mild-moderate hepatic disease (M/MHD), and 6 normal healthy volunteers (NHVs) completed the study. Adverse events were mild to moderate in severity and were mainly limited to headache and expected gastrointestinal symptoms. Serum sulfate levels were highly variable at all times, even after adjusting for baseline. Sulfate was higher in MRD in comparison to the other groups. The Cmax and AUC were highe... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3173298 Tue, 12 Jan 2010 00:00:00 +0100 3173298 http://www.medworm.com/index.php?rid=3173288&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20067943%26dopt%3DAbstract Authors: Elliott ES, Purvis TL, Nelson LA, Sommi RW PMID: 20067943 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3173288 Tue, 12 Jan 2010 00:00:00 +0100 3173288 http://www.medworm.com/index.php?rid=3149718&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20051587%26dopt%3DAbstract Authors: Karhu D, Fradette C, Potgieter MA, Ferreira MM, Terblanché J The pharmacokinetics of a once-daily formulation of tramadol (Tramadol Contramid OAD 200-mg tablets) following single-dose and multiple-dose administration was compared with that of an immediate-release product (tramadol IR 50-mg tablets) in 2 separate studies. In both studies, AUC parameters met bioequivalence criteria, whereas Cmax of Tramadol Contramid OAD was lower than that of tramadol IR following a 200-mg daily dosage. After single-dose administration, the mean tramadol concentration at 1 hour postdose was within the range associated with analgesic efficacy (>100 ng/mL), and the mean concentration remained above this level for the remainder of the dosing interval. Steady state was attained within 48 ho... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3149718 Tue, 05 Jan 2010 00:00:00 +0100 3149718 http://www.medworm.com/index.php?rid=3149717&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20051588%26dopt%3DAbstract Authors: Kaneda K, Baker MT, Han TH, Weeks JB, Todd MM To better understand mannitol pharmacokinetics, the authors constructed and compared population models for high- versus low-dose bolus infusions in humans. Patients (aged 18-75, American Society of Anesthesiologists physical status 1-3) scheduled for elective craniotomy with an anticipated need for intraoperative mannitol were randomly assigned to receive either 0.5 (n = 10) or 1.0 (n = 12) g/kg of 20% mannitol over 15 minutes. Serial blood samples were collected at the predetermined intervals over 12 hours. Plasma mannitol concentrations were measured by gas chromatography and subjected to pharmacokinetic analysis; a 3-compartment model best described mannitol disposition characteristics. Weight and dose were the important covaria... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3149717 Tue, 05 Jan 2010 00:00:00 +0100 3149717 http://www.medworm.com/index.php?rid=3115867&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20023211%26dopt%3DAbstract Authors: Achike FI PMID: 20023211 [PubMed - in process] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3115867 Thu, 24 Dec 2009 07:22:05 +0100 3115867 http://www.medworm.com/index.php?rid=3068024&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19966074%26dopt%3DAbstract This study evaluated the pharmacokinetics of fampridine and its metabolites after administration of fampridine-SR 10 mg in healthy volunteers and in subjects with mild, moderate, or severe renal impairment (5 per group). Analysis of variance was used to calculate 90% confidence intervals (CIs) for the ratios (impaired/healthy) of least squares mean in maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC). Clearance was primarily through urinary excretion. In renally impaired subjects, fampridine plasma concentrations were consistently higher than in healthy individuals: ratios for Cmax ranged from 166.5% to 199.9% for mild and severe renal impairment, respectively. AUC0-infinity ratios ranged from 175.3% to 398.7%, respectively, for mild and severe re... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3068024 Fri, 04 Dec 2009 00:00:00 +0100 3068024 http://www.medworm.com/index.php?rid=3059961&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19955497%26dopt%3DAbstract Authors: Srinivas NR PMID: 19955497 [PubMed - in process] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3059961 Tue, 01 Dec 2009 00:00:00 +0100 3059961 http://www.medworm.com/index.php?rid=3052821&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19952374%26dopt%3DAbstract Authors: Goicoechea M, Jain S, Bi L, Sun S, Smith G, Ha B, Richman D, Louie S, Haubrich R, Treatment Group CC PMID: 19952374 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3052821 Tue, 01 Dec 2009 00:00:00 +0100 3052821 http://www.medworm.com/index.php?rid=3052825&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19948945%26dopt%3DAbstract The objective of this study was to determine if sex influences the pharmacokinetics and hemodynamics of the CYP2D6 substrate metoprolol and its interaction with diphenhydramine (CYP2D6 inhibitor) in healthy young participants with high (extensive metabolizer [EM]) or low (poor metabolizer [PM]) CYP2D6 activities. A prespecified comparative analysis of data from 2 sequential clinical trials that included 16 EM and 4 PM women and 10 EM and 6 PM men was performed. The participants in the 2 trials were administered a single oral dose of 100 mg metoprolol in the presence of steady-state diphenhydramine or placebo. Serial plasma and urine samples were obtained for 48 hours, and hemodynamic data was obtained for 12 hours after metoprolol. In the placebo arm, EM and PM women had 62% and 59% higher... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3052825 Mon, 30 Nov 2009 00:00:00 +0100 3052825 http://www.medworm.com/index.php?rid=3052824&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19948946%26dopt%3DAbstract This study evaluated the effect of grapefruit juice on the pharmacokinetics of nilotinib in 21 healthy male participants. All participants underwent 2 study periods during which they received a single oral dose of 400 mg nilotinib with 240 mL double-strength grapefruit juice or 240 mL water in a crossover fashion. Serial blood samples were collected for the determination of serum nilotinib concentrations by a validated liquid chromatography/tandem mass spectrometry assay. Concurrent intake of grapefruit juice increased the nilotinib peak concentration (Cmax) by 60% and the area under the serum concentration-time curve (AUC0-infinity) by 29% but did not affect the time to reach Cmax or the elimination half-life of nilotinib. The most common adverse events were headache and vomiting, which w... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3052824 Mon, 30 Nov 2009 00:00:00 +0100 3052824 http://www.medworm.com/index.php?rid=3052823&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19948947%26dopt%3DAbstract Authors: Farid NA, Kurihara A, Wrighton S Ticlopidine, clopidogrel, and prasugrel are thienopyridine prodrugs that inhibit adenosine-5'-diphosphate (ADP)-mediated platelet aggregation in vivo. These compounds are converted to thiol-containing active metabolites through a corresponding thiolactone. The 3 compounds differ in their metabolic pathways to their active metabolites in humans. Whereas ticlopidine and clopidogrel are metabolized to their thiolactones in the liver by cytochromes P450, prasugrel proceeds to its thiolactone following hydrolysis by carboxylesterase 2 during absorption, and a portion of prasugrel's active metabolite is also formed by intestinal CYP3A. Both ticlopidine and clopidogrel are subject to major competing metabolic pathways to inactive metabolites. Thus, va... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3052823 Mon, 30 Nov 2009 00:00:00 +0100 3052823 http://www.medworm.com/index.php?rid=3052822&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19948948%26dopt%3DAbstract The objective of this study is to characterize the steady-state pharmacokinetics and compare the relative bioavailability of the extended-release capsule formulation of the antimuscarinic trospium chloride, developed for once-daily administration, and trospium chloride immediate-release tablets. This is a single-center, multidose, randomized, open-label, 2-period, 2-arm crossover, bioavailability study in healthy adult male and female subjects who are within 20% of their ideal body weight. Subjects receive trospium 60-mg extend-ed-release capsules once daily and trospium 20-mg tablets twice daily for 10 days, each in a crossover manner. Twenty-four subjects are enrolled in the study. With multiple dosing of trospium 60 mg extended-release once daily versus 20 mg twice daily, lower geometri... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3052822 Mon, 30 Nov 2009 00:00:00 +0100 3052822 http://www.medworm.com/index.php?rid=3034618&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19940229%26dopt%3DAbstract This study characterized the pharmacokinetics (PK) of golimumab, an antitumor necrosis factor alpha human IgG1kappa monoclonal antibody, after a single intravenous (IV) or subcutaneous (SC) administration in healthy subjects and determined the absolute bioavailability of SC golimumab delivered at 3 different anatomical regions. Seventy-eight healthy adult males were randomly assigned to receive a single dose of golimumab 100 mg by IV (30-minute infusion, n = 23) or SC administration at different sites (upper arm, n = 18; abdomen, n = 18; thigh, n = 19). Serial blood samples were collected for PK characterization. Following IV administration, the mean maximum observed serum golimumab concentration (Cmax) and the mean area under the concentration versus time curves from time zero to infinity... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3034618 Wed, 25 Nov 2009 00:00:00 +0100 3034618 http://www.medworm.com/index.php?rid=3034617&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19940230%26dopt%3DAbstract In conclusion, a previously presented integrated model has been extended to describe glucose and insulin concentrations in healthy volunteers following an OGTT. The characterization of the differences between the healthy and diabetic stages in the IGI model could potentially be used to extrapolate drug effect from healthy volunteers to T2DM. PMID: 19940230 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3034617 Wed, 25 Nov 2009 00:00:00 +0100 3034617 http://www.medworm.com/index.php?rid=3034616&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19940231%26dopt%3DAbstract Authors: Zeng X, Deng Y, Feng Y, Liu Y, Yang L, Huang Y, Sun J, Liang W, Guan Y The pharmacokinetics and safety of ginsenoside Rd (Rd) were assessed in healthy Chinese volunteers. In the single-dose study, a randomized, open-label, 3-way crossover design was used. Participants were assigned to receive 10, 45, or 75 mg Rd by intravenous infusion, with a 2-week washout period between dosing periods. Plasma levels of Rd were found to be proportional to dose, with the mean Cmax and AUC0-infinity ranging from 2.8 to 19.3 mg/L and 27.9 to 212.5 mgh/L over the dose range studied. Ginsenoside Rd was slowly cleared from plasma (t1/2Z = 17.7-19.3 hours). In the multiple-dose study, 10 mg Rd was administered once daily for 6 days. Slight drug accumulation was noted. The mean steady-state Cmax, AU... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3034616 Wed, 25 Nov 2009 00:00:00 +0100 3034616 http://www.medworm.com/index.php?rid=3034615&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19940232%26dopt%3DAbstract Authors: Skerjanec A, Wang J, Maren K, Rojkjaer L Deferasirox, a newly developed iron chelator, was coadministered orally with either a known inducer of drug metabolism or with cosubstrates for cytochrome P450 (CYP) to characterize the potential for drug-drug interactions. In the induction assessment, single-dose deferasirox pharmacokinetics were obtained in the presence and absence of a repeated-dose regimen of rifampin. In the CYP3A interaction evaluation, midazolam and its active hydroxylated metabolite were assessed after single doses of midazolam in the presence and absence of steady-state concentrations of deferasirox. To test for interaction at the level of CPY2C8, single-dose repaglinide pharmacokinetics/pharmacodynamics were determined with and without repeated-dose administra... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3034615 Wed, 25 Nov 2009 00:00:00 +0100 3034615 http://www.medworm.com/index.php?rid=3034614&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19940233%26dopt%3DAbstract This study investigates whether aspirin induces esophageal mucosal injury and whether a proton-pump inhibitor can prevent such injury in relation to CYP2C19 genotypes. Fifteen healthy Japanese volunteers are dosed for 7 days in a 5-way randomly crossover trial: placebo, aspirin 100 mg, rabeprazole 10 mg, and aspirin 100 mg plus rabeprazole 10 mg either once daily or 4 times per day. All subjects undergo endoscopy and 24-hour intragastric pH monitoring on day 7. With the aspirin regimen, esophageal mucosal disorders occur in 7 patients (46.7%) (5, grade M; 2, grade A). The median 24-hour pH differs significantly among subjects who develop grade M or A gastroesophageal reflux disease and those who do not develop gastroesophageal reflux disease; the median pH in grade A gastroesophageal reflu... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3034614 Wed, 25 Nov 2009 00:00:00 +0100 3034614 http://www.medworm.com/index.php?rid=3027265&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19934028%26dopt%3DAbstract Authors: Werner U, Werner D, Heinbüchner S, Graf B, Ince H, Kische S, Thürmann P, König J, Fromm MF, Zolk O Signals from pharmacovigilance studies indicate that women are at higher risk for adverse drug reactions (ADRs) due to diuretics. Despite the long-term use of torasemide, there are few studies investigating gender differences of torasemide pharmacokinetics in the hospital setting. Therefore, torasemide pharmacokinetics were investigated in 90 patients (45 women, 45 men) during steady-state conditions. Torasemide elimination was significantly reduced in women compared with men (eg, body-weight-normalized area under the concentration-time curve: 42.1 +/-20.4 vs 30.9 +/-10.3 kg*h/L; P <.001). Among the investigated genetic factors [SLC22A11(OAT4), SLCO1B1(OATP1B1),... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3027265 Mon, 23 Nov 2009 00:00:00 +0100 3027265 http://www.medworm.com/index.php?rid=3027264&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19934029%26dopt%3DAbstract Authors: Gu J, Noe A, Chandra P, Al-Fayoumi S, Ligueros-Saylan M, Sarangapani R, Maahs S, Ksander G, Rigel DF, Jeng AY, Lin TH, Zheng W, Dole WP Angiotensin receptor blockade and neprilysin (NEP) inhibition together offer potential benefits for the treatment of hypertension and heart failure. LCZ696 is a novel single molecule comprising molecular moieties of valsartan and NEP inhibitor prodrug AHU377 (1:1 ratio). Oral administration of LCZ696 caused dose-dependent increases in atrial natriuretic peptide immunoreactivity (due to NEP inhibition) in Sprague-Dawley rats and provided sustained, dose-dependent blood pressure reductions in hypertensive double-transgenic rats. In healthy participants, a randomized, double-blind, placebo-controlled study (n = 80) of single-dose (200-1200 mg) an... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3027264 Mon, 23 Nov 2009 00:00:00 +0100 3027264 http://www.medworm.com/index.php?rid=3027263&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19934030%26dopt%3DAbstract The objective of this study was to perform exposure-response modeling to increase the understanding of reduction in disease severity following treatment with ustekinumab in patients with moderate to severe psoriasis who participate in two phase III studies (PHOENIX 1 and PHOENIX 2). Patients were randomly assigned to receive ustekinumab 45 mg or 90 mg (n = 1312; 11 624 Psoriasis Area and Severity Index [PASI] scores) or placebo (n = 665; 3278 PASI scores). Disease severity was assessed using PASI scores. A population mechanism-based exposure-response model of ustekinumab using NONMEM was developed using serum ustekinumab concentrations and PASI scores. The pharmacodynamic response effect was the reduction in PASI score. The placebo effect, although minor, was also integrated into the model... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3027263 Mon, 23 Nov 2009 00:00:00 +0100 3027263 http://www.medworm.com/index.php?rid=3027262&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19934031%26dopt%3DAbstract This report describes population pharmacokinetics/ pharmacodynamic (PK/PD) modeling of serum otelixizumab concentrations, changes in CD4+ and CD8+ T-cell counts, and modulation and saturation of CD3/T-cell receptors (TCR) (determined by flow cytometry) after IV administration of otelixizumab in subjects with either type 1 diabetes or psoriasis. Otelixizumab PK were monoexponential with Michaelis-Menten elimination. Nonlinearity was manifested at high concentrations (Km = 0.968 mug/mL). Lymphocyte dynamics were captured by an indirect response model simplified to direct inhibition. In diabetic subjects, the otelixizumab serum concentration producing a 50% decrease in peripheral blood counts was 0.0187 mug/mL for CD4+ T cells and 0.0120 mug/mL for CD8+ T cells. Corresponding values for psori... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3027262 Mon, 23 Nov 2009 00:00:00 +0100 3027262 http://www.medworm.com/index.php?rid=3004686&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19915180%26dopt%3DAbstract The objective of this study was to evaluate appropriate desirudin dosing in moderate renal impairment and the effect of desirudin on aPTT in moderate renal impairment. Desirudin plasma concentration and aPTT data were extracted from 6 studies. Participants with normal renal function or moderate renal impairment (creatinine clearance [ClCr] 31-60 mL/min) were included. Pharmacokinetic and Monte Carlo simulations were done. After administration of desirudin 15 mg every 12 hours subcutaneously (SC) to steady state, peak desirudin concentrations were 35 and 47 nmol/L in the normal and moderate renal function groups, respectively. Monte Carlo simulations found median 2-hour Cmax concentrations of 51.7 nmol/L in normal renal function and 52.4 nmol/L in moderate renal impairment. Desirudin exhibi... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3004686 Fri, 13 Nov 2009 00:00:00 +0100 3004686 http://www.medworm.com/index.php?rid=3004685&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19915181%26dopt%3DAbstract The objective of this randomized, double-blind, placebo-controlled, dose escalation study was to determine the pharmacokinetic characteristics, safety, and tolerability of single doses of inhaled loxapine aerosol in healthy volunteers. Loxapine was delivered by means of a unique thermally generated aerosol comprising drug particles of a size designed for deep lung delivery and absorption. Fifty participants were randomized to receive 0.625, 1.25, 2.5, 5.0, or 10 mg of loxapine aerosol or placebo. Following inhalation, the tmax median (25%, 75%) was 2 (1, 3) minutes. The loxapine AUCinfinity was dose proportional across all doses with slope (90% confidence interval) of log AUCinfinity versus log dose = 0.909 (0.832, 0.987). No clinically meaningful changes were noted in hematology results, ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=3004685 Fri, 13 Nov 2009 00:00:00 +0100 3004685 http://www.medworm.com/index.php?rid=2981077&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19897763%26dopt%3DAbstract This study evaluated the factors associated with adherence with angiotensin-converting enzyme inhibitors (ACEIs), an increasingly common antihypertensive drug of choice. The authors included all adult patients who were prescribed an ACEI and paid at least 2 consecutive visits to any primary care clinics of one large territory of Hong Kong from January 2004 to June 2007. The determinants of good adherence to ACEI, as defined by a medication possession ratio >/=80%, were evaluated by multivariate regression analysis. From 6408 eligible patients, 88.0% were adherent. Patients attending family medicine specialist clinics (adjusted odds ratio [AOR] = 1.46, 95% confidence interval [CI]: 1.12-1.91, P = .005) and follow-up visitors (AOR = 2.98, 95% CI: 2.49-3.55, P < .001) were significantly... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2981077 Fri, 06 Nov 2009 00:00:00 +0100 2981077 http://www.medworm.com/index.php?rid=2981076&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19897764%26dopt%3DAbstract The objectives of this study are to characterize the pharmacokinetics and explore the pharmacodynamics of acyclovir in plasma and oral washings of 8 subjects receiving 7 days of valacyclovir 1500 mg twice daily for EBV infectious mononucleosis. Virologic and clinical responses are assessed over 12 days. Acyclovir is measured by liquid chromatography/ultraviolet detection. EBV DNA is quantitated by TaqMan polymerase chain reaction. NONMEM VI and linear regression are used for data analysis. Acyclovir profiles in plasma and oral washings are consistent with a 1-compartment model. Final model estimates of clearance, volume of distribution, and fraction of acyclovir in oral wash supernatant are 49.9 L/h, 74.1 L, and 1.14%, respectively. The quantity of EBV DNA in oral washings and blood, and t... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2981076 Fri, 06 Nov 2009 00:00:00 +0100 2981076 http://www.medworm.com/index.php?rid=2981075&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19897765%26dopt%3DAbstract Authors: Fujita T, Kumagai Y, Nakahara I, Ohtani Y, Majima M PMID: 19897765 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2981075 Fri, 06 Nov 2009 00:00:00 +0100 2981075 http://www.medworm.com/index.php?rid=2921029&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19843656%26dopt%3DAbstract Authors: Chapel S, Hutmacher MM, Haig G, Bockbrader H, de Greef R, Preskorn SH, Lalonde RL An exposure-response (E-R) analysis using linear mixed effects modeling was conducted on data from a thorough QTc trial for asenapine in 148 patients with schizophrenia. In a parallel design, patients received asenapine 5 mg twice daily (BID) for 10 days (10d) followed by 10 mg BID (6d), asenapine 15 mg BID (10d) followed by 20 mg BID (6d), quetiapine 375 mg BID (for assay sensitivity; 16d) or placebo (16d). Triplicate 12-lead electrocardiograms and concentration measurements were obtained on day -1 (baseline), 1, 10, and 16 at 8 scheduled times on each day. At mean C(max) for all asenapine doses, the E-R model predicted that the mean QTcF increase was less than 5 milliseconds, the International ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2921029 Sat, 24 Oct 2009 04:50:08 +0100 2921029 http://www.medworm.com/index.php?rid=2921028&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19843657%26dopt%3DAbstract This study investigates repolarization changes induced by a new candidate drug to determine whether a composite electrocardiographic (ECG) measure of T-wave morphology could be used as a reliable marker to support the evidence of abnormal repolarization, which is indicated by QT interval prolongation. Seventy-nine healthy subjects were included in this parallel study. After a baseline day during which no drug was given, 40 subjects received an I(Kr)-blocking antipsychotic compound (Lu 35-138) on 7 consecutive days while 39 subjects received placebo. Resting ECGs were recorded and used to determine a combined measure of repolarization morphology (morphology combination score [MCS]), based on asymmetry, flatness, and notching. Replicate measurements were used to determine reliable change and... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2921028 Sat, 24 Oct 2009 04:50:05 +0100 2921028 http://www.medworm.com/index.php?rid=2921030&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19843655%26dopt%3DAbstract Authors: Jin Y, Pollock BG, Coley K, Miller D, Marder SR, Florian J, Schneider L, Lieberman J, Kirshner M, Bies RR The goal of the study was to characterize population pharmacokinetics (PPK) for perphenazine in patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Patients (n = 156) received 8 to 32 mg of perphenazine daily for 14 to 600 days for a total of 421 plasma concentrations measurements. Nonlinear mixed-effects modeling was used to determine PPK characteristics of perphenazine. One- and 2-compartment models with various random effect implementations and mixture distributions were evaluated. Objective function values and goodness-of-fit plots were used as model selection criteria. Age, weight, sex, race, smoking, and concomita... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2921030 Mon, 19 Oct 2009 23:00:00 +0100 2921030 http://www.medworm.com/index.php?rid=2913287&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19841156%26dopt%3DAbstract Authors: Jin Y, Pollock BG, Frank E, Cassano GB, Rucci P, Müller DJ, Kennedy JL, Forgione RN, Kirshner M, Kepple G, Fagiolini A, Kupfer DJ, Bies RR The purpose of this study was to characterize escitalopram population pharmacokinetics (PK) in patients treated for major depression in a cross-national, US-Italian clinical trial. Data from the 2 sites participating in this trial, conducted at Pittsburgh (United States) and Pisa (Italy), were used. Patients received 5, 10, 15, or 20 mg of escitalopram daily for a minimum of 32 weeks. Nonlinear mixed effects modeling was used to model the PK characteristics of escitalopram. One- and 2-compartment models with various random effect implementations were evaluated during model development. Objective function values and goodness-of-fit plot... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2913287 Sun, 18 Oct 2009 23:00:00 +0100 2913287 http://www.medworm.com/index.php?rid=2913286&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19841157%26dopt%3DAbstract Authors: Kienzler JL, Gold M, Nollevaux F Systemic bioavailability and pharmacodynamics of topical diclofenac sodium gel 1% were compared with those of oral diclofenac sodium 50-mg tablets. In a randomized, 3-way crossover study, healthy volunteers (n = 40) received three 7-day diclofenac regimens: (A) 16 g gel applied as 4 g to 1 knee 4 times daily (4 g on surface area 400 cm(2)), (B) 48 g gel applied as 4 g per knee 4 times daily to 2 knees plus 2 g gel per hand applied 4 times daily to 2 hands (12 g on 1200 cm(2)), and (C) 150 mg oral diclofenac applied as 50-mg tablets 3 times daily. Thirty-nine participants completed all 3 regimens. Systemic exposure was greater with oral diclofenac (AUC0-24, 3890 +/- 1710 ngh/mL) than with topical treatments A (AUC0-24, 233 +/- 128 ngh/mL) and B ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2913286 Sun, 18 Oct 2009 23:00:00 +0100 2913286 http://www.medworm.com/index.php?rid=2913285&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19841158%26dopt%3DAbstract Authors: Hawke RL, Schrieber SJ, Soule TA, Wen Z, Smith PC, Reddy KR, Wahed AS, Belle SH, Afdhal NH, Navarro VJ, Berman J, Liu QY, Doo E, Fried MW Silymarin, derived from the milk thistle plant Silybum marianum, is widely used for self-treatment of liver diseases, including hepatitis C virus (HCV), and its antiviral activity has been demonstrated in vitro and in HCV patients administered an intravenous formulation of the major silymarin flavonolignans, silybin A and silybin B. The safety and dose-exposure relationships of higher than customary oral doses of silymarin and its acute effects on serum HCV RNA were evaluated in noncirrhotic HCV patients. Four cohorts of 8 patients with well-compensated, chronic noncirrhotic HCV who failed interferonbased therapy were randomized 3:1 to silym... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2913285 Sun, 18 Oct 2009 23:00:00 +0100 2913285 http://www.medworm.com/index.php?rid=2913284&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19841159%26dopt%3DAbstract Authors: Shon JH, Yeo CW, Liu KH, Lee SS, Cha IJ, Shin JG The present study was performed to elucidate the effects of itraconazole and rifampin on the pharmacokinetics and pharmacodynamics of ebastine, a nonsedative H1 receptor antagonist. In a 3-way crossover sequential design with 2-week washouts, 10 healthy participants were pretreated with itraconazole for 6 days, rifampin for 10 days, or neither. After oral administration of 20 mg ebastine, blood and urine samples were collected for 72 and 24 hours, respectively, and histamine-induced wheal and flare reactions were measured to assess the antihistamine response for 12 hours. Itraconazole pretreatment decreased the oral clearance of ebastine to 10% (P < .001) and increased the AUCinfinity of the active metabolite, carebastine, by... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2913284 Sun, 18 Oct 2009 23:00:00 +0100 2913284 http://www.medworm.com/index.php?rid=2913283&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19841160%26dopt%3DAbstract In this study, the effects of 2 treatments are compared: lisinopril alone versus lisinopril + simvastatin, on erythrocyte antioxidant and energy metabolic enzymes. Patients with atherosclerosis and moderate hypertension are randomly assigned to receive lisinopril 10 to 20 mg/d or lisinopril 10 to 20 mg/d plus simvastatin 20 mg/d for 24 weeks. Higher catalase activity and lower glutathione peroxidase activity are observed in 94% to 100% patients from both groups after 12 and 24 weeks of treatment. Superoxide dismutase activity is increased significantly only after 24 weeks. No changes of glutathione reductase, lactate dehydrogenase, and phosphofructokinase activities are found under any conditions indicated. Both treatments decrease systolic and diastolic blood pressure equally. Only lisino... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2913283 Sun, 18 Oct 2009 23:00:00 +0100 2913283 http://www.medworm.com/index.php?rid=2913282&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19841161%26dopt%3DAbstract Authors: Cawello W, Nickel B, Eggert-Formella A Lacosamide is a new antiepileptic drug for adjunctive treatment of adult partial-onset seizures. Two open-label, multiple-dose clinical trials were conducted to evaluate the potential for pharmacokinetic interaction between lacos amide and carbamazepine. The influence of carbamazepine on lacosamide pharmacokinetics (trial A) and lacosamide on carbamazepine pharmacokinetics (trial B) was investi gated in 19 (trial A) and 18 (trial B) healthy male partici pants. Trial A participants received lacosamide 200 mg bid alone and with carbamazepine 200 mg bid. Trial B partici pants received carbamazepine 200 mg bid alone and with lacosamide 200 mg bid. Pharmacokinetic parameters, area under the concentration-time curve during a dosage interval at ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2913282 Sun, 18 Oct 2009 23:00:00 +0100 2913282 http://www.medworm.com/index.php?rid=2905637&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19837906%26dopt%3DAbstract In conclusion, EC145 is rapidly distributed and eliminated in cancer patients. BSA is a statistically significant covariate on EC145 clearance, but its clinical relevance remains to be defined. EC145-induced constipation occurs at a higher frequency in the patients with lower EC145 clearance, where the drug exposure tends to be higher. PMID: 19837906 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2905637 Thu, 15 Oct 2009 23:00:00 +0100 2905637 http://www.medworm.com/index.php?rid=2905636&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19837907%26dopt%3DAbstract Authors: Ling J, Zhou H, Jiao Q, Davis HM The authors evaluated interspecies scaling for the prediction of human clearance of 18 therapeutic monoclonal antibodies (mAbs). Human and monkey/chimpanzee data of 14 mAbs were classified based on the targeted antigens (soluble or membrane bound). Simple allometry and/or a time-invariant method (elementary Dedrick plot) were performed. Results indicate that human clearance might be accurately predicted from monkey data for mAbs targeting soluble receptors or membrane-bound receptors with limited tissue distribution using simplified allometry. The optimal exponents were estimated to be 0.85 or If nonlinearity is anticipated at the human efficacious dose, pharmacokinetic parameters obtained at high doses in animals might not be sufficient for fu... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2905636 Thu, 15 Oct 2009 23:00:00 +0100 2905636 http://www.medworm.com/index.php?rid=2905635&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19837908%26dopt%3DAbstract In conclusion, drugs that are substrates of BCRP and MRP4, like zidovudine, may have an altered efficacy in newborns. PMID: 19837908 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2905635 Thu, 15 Oct 2009 23:00:00 +0100 2905635 http://www.medworm.com/index.php?rid=2902949&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19833860%26dopt%3DAbstract This study therefore met the criteria for a negative thorough QT study. Telbivudine had no adverse effect on cardiac repolarization in healthy participants, even at supratherapeutic exposure, suggesting a broad safety margin. PMID: 19833860 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2902949 Wed, 14 Oct 2009 23:00:00 +0100 2902949 http://www.medworm.com/index.php?rid=2902947&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19833861%26dopt%3DAbstract Authors: Lauring B, Dishy V, Luo WL, Laterza O, Patterson J, Cote J, Chao A, Larson P, Gutierrez M, Wagner JA, Lai E Laropiprant, an antagonist of the PGD2 receptor, DP1, is effective in reducing the flushing symptoms associated with extended-release (ER) niacin and thereby improves the tolerability of niacin therapy for dyslipidemia. Because PGD2 has been reported to inhibit platelet aggregation in vitro, it has been speculated that antagonism of DP1 may enhance platelet reactivity. Three clinical studies evaluated the potential effect of laropiprant, with or without coadministration of ER niacin, on in vivo platelet function in healthy subjects and hypercholesterolemic or diabetic subjects by measuring urinary levels of 11-dehydrothromboxane B2 (11-dTxB2), a marker of in vivo platele... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2902947 Wed, 14 Oct 2009 23:00:00 +0100 2902947 http://www.medworm.com/index.php?rid=2899405&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19826060%26dopt%3DAbstract Authors: Vakily M, Wu J, Atkinson SN The effect of the proton pump inhibitor dexlansoprazole, an enantiomer of lansoprazole, on QT intervals was assessed after oral administration of a modifiedrelease formulation of dexlansoprazole (dexlansoprazole MR). In this randomized, positivecomparator, placebocontrolled, 4period crossover study, 40 healthy participants received single doses of dexlansoprazole MR 90 mg, dexlansoprazole MR 300 mg, moxifloxacin 400 mg, and placebo separated by 5day washout intervals. Twentyfourhour electrocardiograms were obtained at baseline and during each dosing period. The number and percentage of participants experiencing an increase in QT interval from baseline to maximum postdose value were evaluated during each dosing regimen, and pharmacokinetic profiles o... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2899405 Mon, 12 Oct 2009 23:00:00 +0100 2899405 http://www.medworm.com/index.php?rid=2873081&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19808950%26dopt%3DAbstract The objective of this study was to investigate the gene expression signature of monocyte/macrophages and the pleiotropic effects of atorvastatin on monocytes in atherosclerotic patients. Forty patients with coronary heart diseases were randomly assigned to double-blind therapy with either 20 or 80 mg per day of atorvastatin. Follow-up visits occurred at weeks 6 and 12, including complete chemistry and lipid analyses and quantification of 14 target genes in monocytes. After 12 weeks of therapy, both groups gained beneficial alterations in lipid profiles. Both groups experienced significant reductions in gene expression of lipoprotein-associated phospholipase A2, CD13, leptin receptor, matrix metalloproteases-1, legumain, and prolyl oligopeptidase after 12 weeks of therapy. Only tumor protei... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2873081 Mon, 05 Oct 2009 23:00:00 +0100 2873081 http://www.medworm.com/index.php?rid=2873080&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19808951%26dopt%3DAbstract Authors: Curtis KK, Hartney JT, Jewell RC, Park JW, Lebowitz PF, Griffin PP, Borad MJ, Fitch TR, Northfelt DW Topotecan pharmacokinetics at higher infusion rates (4 mg/m(2) over 30 minutes) have not been studied. The authors report a pharmacokinetics and safety study of this dose in advanced cancer patients. Sixteen patients were given a 4-mg/m(2) topotecan infusion intravenously (IV) over 30 minutes weekly for 3 weeks, repeated every 28 days. Pharmacokinetics were determined after the first dose. Plasma concentrations of total topotecan were measured to derive CL, V, C, t, t1/2, AUC0-t, and AUC0-infinity. Plasma total topotecan concentrations decreased biexponentially, with a mean CL value of 20.6 L/h, Vss value of 101 L, and t1/2 value of 5.0 h. Nine significant adverse events (all h... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2873080 Mon, 05 Oct 2009 23:00:00 +0100 2873080 http://www.medworm.com/index.php?rid=2873079&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19808952%26dopt%3DAbstract Authors: Takahashi N, Inui N, Morita H, Takeuchi K, Uchida S, Watanabe H, Nakamura H Thyroid hormones have been shown to reduce the activity and expression of cytochrome P450 (CYP) 3A4 in vitro. The influence of thyroid hormone on drug action via a CYP3A-dependent pathway has not been elucidated in humans. This is the first report showing the effect of thy roid hormone on CYP3A enzyme activity in humans. Ten healthy volunteers participate in this open-label study, in which the pharmacokinetics of midazolam and the urinary ratios of 6 beta-hydroxycortisol/free cortisol before and after 2 weeks of oral administration of triiodothyronine were compared. Triiodothyronine administration significantly reduced the area under the concentration-time curve ratios for 1'-hydroxymidazolam/midazolam... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2873079 Mon, 05 Oct 2009 23:00:00 +0100 2873079 http://www.medworm.com/index.php?rid=2856834&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19797535%26dopt%3DAbstract The objective of this study was to characterize the pharmacokinetics of alvimopan and metabolite before, during, and after administration of a short course of antibiotics in healthy adult participants. Simulations were conducted to determine the feasibility for this study. An open-label, sequential drug interaction study was conducted in 45 participants who received twice-daily dosing of alvimopan with and without ciprofloxacin. Metabolite concentrations were reduced by 99.2% (90% confidence interval: 98.8-99.5) in the presence of ciprofloxacin. The interaction occurred rapidly, and recovery was slow. The interaction may be of relevance for patients with relatively high metabolite plasma concentrations prior to antibiotic administration but of little relevance for patients with little or n... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2856834 Wed, 30 Sep 2009 23:00:00 +0100 2856834 http://www.medworm.com/index.php?rid=2856833&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19797536%26dopt%3DAbstract Authors: Nunes T, Almeida L, Rocha JF, Falcão A, Fernandes-Lopes C, Loureiro AI, Wright L, Vaz-da-Silva M, Soares-da-Silva P PMID: 19797536 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2856833 Wed, 30 Sep 2009 23:00:00 +0100 2856833 http://www.medworm.com/index.php?rid=2856832&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19797537%26dopt%3DAbstract Authors: Hughes DA, Aronson JK There is a log-linear relation between the dose and duration of action of drugs with single-compartment pharmacokinetics and direct, reversible mechanisms of action. However, it has been suggested that this relation does not extend to drugs whose metabolites are active or slowly eliminated, drugs with saturable kinetics, and drugs with hit-and-run effects. The purpose of this study is to test this hypothesis and to quantify the relationship by way of a systematic review coupled to an empirical analysis. All issues of 4 clinical pharmacology journals from 1980 to 2005 are hand-searched for articles that present pharmacodynamic response versus time curves for 4 or more different doses. Data on duration of action, dose, and area under the plasma concentratio... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2856832 Wed, 30 Sep 2009 23:00:00 +0100 2856832 http://www.medworm.com/index.php?rid=2856831&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19797538%26dopt%3DAbstract Authors: Italia KY, Jijina FF, S C, Nadkarni AH, Sawant P, Ghosh K, Colah RB Hydroxyurea, used in the treatment of sickle cell anemia, is a teratogenic drug. However, the potential benefits of the drug far outweigh its risks when the fetus of the patient on hydroxyurea therapy gets exposed to the drug in an unplanned pregnancy. The authors present 2 clinically severe cases of patients with sickle-beta thalas semia who became pregnant while on hydroxyurea therapy and delivered healthy babies. Hydroxyurea was stopped after the confirmation of the pregnancy and was restarted after the termination of breastfeeding. Seven cases of fetal exposure to hydroxyurea have been reported among sickle cell anemia patients. More such data are required to confirm the effect of hydroxyurea exposure on t... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2856831 Wed, 30 Sep 2009 23:00:00 +0100 2856831 http://www.medworm.com/index.php?rid=2843128&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19783710%26dopt%3DAbstract Authors: Wright DH, Herman GA, Maes A, Liu Q, Johnson-Levonas AO, Wagner JA Sitagliptin is an orally active, highly selective dipeptidyl peptidase IV (DPP-4) inhibitor for treatment of type 2 diabetes mellitus. This randomized, open-label, 2-part, 2-period crossover study assessed pharmacokinetics/pharmacodynamics of warfarin in the presence/absence of multiple-dose sitagliptin. Twelve participants received treatments A and B separated by >7-day washout: treatment A involved coadministration of sitagliptin 200 mg/d for 11 days (days 1-11) and warfarin 30 mg on day 5, and treatment B involved warfarin 30 mg alone on day 1. R(+) warfarin, S(-) warfarin, and international normalized ratio (INR) were assayed predose and up to 168 hours postdose. The geometric mean ratios (GMRs; warfarin... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2843128 Wed, 30 Sep 2009 00:51:24 +0100 2843128 http://www.medworm.com/index.php?rid=2843127&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19783711%26dopt%3DAbstract This study sought to determine whether the presence of in vitro anticholinergic activity (AA) among different drugs is associated with reporting of neuropsychiatric adverse events (NPAEs) and whether age affects this relationship. Retrospective case/noncase analyses using Australia's spontaneous Adverse Drug Reaction System (ADRS) database containing 150 475 reports determined crude and adjusted reporting odds ratios (RORs) for NPAEs for 23 drugs with various reported in vitro AA. Covariates were age (treated as a dichotomous variable [>/=65 years]), gender, and concomitant use of antipsychotics, benzodiazepines, tricyclic antidepressants, and drugs with recognized inherent anticholinergic properties (anticholinergic drugs). The interaction effect between these covariates and each drug ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2843127 Wed, 30 Sep 2009 00:51:16 +0100 2843127 http://www.medworm.com/index.php?rid=2843121&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19783712%26dopt%3DAbstract Authors: Walker JR, Brown K, Rohatagi S, Bathala MS, Xu C, Wickremasingha PK, Salazar DE, Mager DE Quantitative structure-property relationship (QSPR) models were developed to correlate physicochemical properties of structurally unrelated drugs with extent of in vitro binding to colesevelam, and predicted values were compared with drug exposure changes in vivo following coadministration. The binding of 17 drugs to colesevelam was determined by an in vitro dissolution drug-binding assay. Data from several clinical studies in healthy volunteers to support administration of colesevelam in diabetic patients were also collected along with existing in vivo literature data and compared with in vitro results. Steric, electronic, and hydrophobic descriptors were calculated for test compounds, a... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2843121 Wed, 30 Sep 2009 00:51:06 +0100 2843121 http://www.medworm.com/index.php?rid=2843118&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19783713%26dopt%3DAbstract Authors: Rupprecht K, Schmidt C, Raspé A, Schweda F, Shipkova M, Fischer W, Bucher M, Kees F, Faerber L The influence of pantoprazole 40 mg twice daily on the bioavailability of a single dose of mycophenolate mofetil 1000 mg or enteric-coated mycophenolate sodium is investigated in healthy volunteers. The plasma concentrations of mycophenolic acid and of the inactive metabolite mycophenolic acid glucuronide are measured by high-performance liquid chromatography. The pharmacokinetic parameters following sole administration are similar for mycophenolate mofetil and enteric-coated mycophenolate sodium except for the time to peak concentration, which is longer in the enteric-coated mycophenolate sodium group. Concomitant treatment with pantoprazole significantly (P < .001) lowers t... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2843118 Wed, 30 Sep 2009 00:50:57 +0100 2843118 http://www.medworm.com/index.php?rid=2843117&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19783714%26dopt%3DAbstract Authors: Schwartz JI, Agrawal NG, Wong PH, Miller J, Bachmann K, Marbury T, Hoelscher D, Cavanaugh PF, Gottesdiener K The authors designed 2 randomized controlled studies to examine the effects of etoricoxib 60 to 120 mg daily on methotrexate pharmacokinetics in 50 rheumatoid arthritis (RA) patients on stable doses of methotrexate (7.5-20 mg). Patients received oral methotrexate at baseline and on days 7 and 14. In study 1, patients received etoricoxib 60 mg (days 1-7) and then 120 mg (days 8-14); in study 2, patients received etoricoxib 90 mg (days 1-7) and then 120 mg (days 8-14). For study 1, the AUC(0-infinity) geometric mean ratio (GMR) (90% confidence interval [CI]) for day 7 versus baseline was 1.01 (0.91, 1.12) for etoricoxib 60 mg; the area under the plasma concentration-time ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2843117 Wed, 30 Sep 2009 00:50:47 +0100 2843117 http://www.medworm.com/index.php?rid=2843115&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19783715%26dopt%3DAbstract This study assessed the potential pharmacokinetic interaction and safety/tolerability of taranabant and phentermine coadministration. This was a randomized, double-blind, 3-panel, fixed-sequence study in healthy participants. Panels A, B, and C evaluated the safety/tolerability of phentermine 15 mg coadministered with taranabant 0.5, 1, and 2 mg for 7 days (panel A) and 28 days (panels B and C). In panels A and C, phentermine 15 mg was administered both with (7 days, panel A; 28 days, panel C) and without (7 days) taranabant 0.5 mg or 2 mg to evaluate pharmacokinetics. The primary endpoint was phentermine AUC(0-24 h) in panels A and C. Secondary endpoints were changes from baseline in blood pressure and heart rate for all panels. The geometric mean ratios and 90% confidence intervals for p... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2843115 Wed, 30 Sep 2009 00:50:31 +0100 2843115 http://www.medworm.com/index.php?rid=2836466&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19779037%26dopt%3DAbstract Authors: Akers WS, Oh JJ, Oestreich JH, Ferraris S, Wethington M, Steinhubl SR The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of cangrelor administered as an intravenous bolus plus a continuous infusion in healthy volunteers. Twenty-two healthy volunteers are randomized to receive 1 of 2 intravenous cangrelor dosing regimens: a 15-microg/kg bolus followed by a 2-microg/kg/ min infusion or a 30-microg/kg bolus followed by a 4-microg/kg/min infusion. The infusion is continued for 60 minutes, and serial blood samples are obtained for evaluation of pharmacokinetic and pharmacodynamic parameters. Administration of an intravenous bolus followed by a continuous infusion rapidly achieves maximum concentrations of cangrelor that are ass... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2836466 Wed, 23 Sep 2009 23:00:00 +0100 2836466 http://www.medworm.com/index.php?rid=2836465&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19779038%26dopt%3DAbstract Authors: Khosravan R, Toh M, Garrett M, La Fargue J, Ni G, Marbury TC, Swan SK, Lunde NM, Bello CL This phase I, open-label, single-dose study evaluates the effects of severe renal impairment and end-stage renal disease (ESRD) requiring hemodialysis on the pharmacokinetics, safety, and tolerability of sunitinib and its primary active metabolite, SU12662. Subjects with normal renal function (creatinine clearance > 80 mL/min), severe renal impairment (creatinine clearance < 30 mL/min), and ESRD requiring hemodialysis receive a single dose of sunitinib 50 mg. Serial blood samples are collected for quantification of plasma concentrations using a validated liquid chromatography with tandem mass spectrometry assay. Safety is monitored. Twenty-four subjects complete the study. Pharmacok... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2836465 Wed, 23 Sep 2009 23:00:00 +0100 2836465 http://www.medworm.com/index.php?rid=2832811&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19776292%26dopt%3DAbstract Authors: Ide T, Sasaki T, Maeda K, Higuchi S, Sugiyama Y, Ieiri I The aims of this study were to develop a population pharmacokinetic (PPK) model for pravastatin pharmacokinetics with regard to enterohepatic circulation (EHC) and to evaluate effects of polymorphisms in SLCO1B1 and ABCC2 on the pharmacokinetic (PK) profile of pravastatin quantitatively. A total of 636 blood samples from 57 healthy male volunteers were used. The PPK analysis was carried out using nonlinear mixed effect modeling (NONMEM) and validated by a bootstrap analysis. The PK profile of pravastatin was best described by a model of EHC with Erlang's distribution. A covariate analysis revealed that SLCO1B1*15 significantly influenced relative bioavailability (Frel); Frel was increased 1.50- and 1.95-fold in participa... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2832811 Tue, 22 Sep 2009 23:00:00 +0100 2832811 http://www.medworm.com/index.php?rid=2832810&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19776293%26dopt%3DAbstract Authors: Zhou XJ, Garner RC, Nicholson S, Kissling CJ, Mayers D IDX899 and IDX989 are new non-nucleoside reversetranscriptase inhibitors (NNRTIs) that exhibit potent inhibition of HIV-1 replication, including NNRTI-resistant mutants. This microdose study investigates the pharmacokinetics and determined oral bioavailability. For each compound, 4 healthy male subjects are randomized to receive via a crossover design a single 100-microg oral and intravenous dose together with 100 nCi of [(14)C]-labeled drug. Plasma and urine samples are obtained over a period of 168 hours postdose and analyzed for total, unchanged drug and major metabolites using an accelerator mass spectrometry method. Based on total radioactivity, oral absorption is near complete. For the parent drug, mean absolute bioa... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2832810 Tue, 22 Sep 2009 23:00:00 +0100 2832810 http://www.medworm.com/index.php?rid=2825233&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19773524%26dopt%3DAbstract In conclusion, the interaction between meropenem and VPA causes a significant decrease in VPA plasma concentration, apparently within 24 hours. As the therapeutic effects of VPA are plasma concentration dependent, the data suggest that these drugs should not be administered concomitantly. PMID: 19773524 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2825233 Mon, 21 Sep 2009 23:00:00 +0100 2825233 http://www.medworm.com/index.php?rid=2825232&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19773525%26dopt%3DAbstract Authors: Marier JF, Mouksassi MS, Gosselin NH, Beliveau M, Cyran J, Wallens J Teduglutide is a GLP-2 analog currently evaluated for the treatment of short bowel syndrome, Crohn's disease, and other gastrointestinal disorders. The population pharmacokinetics (PK) of teduglutide were assessed following daily subcutaneous (SC) administrations of 2.5 to 80 mg doses in a total of 256 patients. A 1-compartment model with a site-specific rate constant of absorption in the abdomen, arm, and thigh was used to assess the PK of teduglutide. Apparent clearance (CL/F) of teduglutide in male participants was approximately 18% higher than that observed in female participants (12.4 vs 10.5 L/h, respectively). Body weight was detected as a significant covariate explaining the volume of distribution of ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2825232 Mon, 21 Sep 2009 23:00:00 +0100 2825232 http://www.medworm.com/index.php?rid=2808155&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19755414%26dopt%3DAbstract In conclusion, telithromycin clearly reduces the N-demethylation of oxycodone to noroxycodone by inhibiting the CYP450 3A4 enzyme. The use of telithromycin in patients receiving multiple doses of oxycodone for pain relief may increase the risk of opioid adverse effects. Reduction of oxycodone dose by 25% to 50% followed by readjustment according to the clinical response might be appropriate. PMID: 19755414 [PubMed - as supplied by publisher] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2808155 Mon, 14 Sep 2009 23:00:00 +0100 2808155 http://www.medworm.com/index.php?rid=2808154&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19755415%26dopt%3DAbstract This study investigated the acute pharmacodynamic effects of sildenafil in patients with pulmonary arterial hypertension (PAH) and concomitant bosentan treatment, in view of a mutual pharmacokinetic interaction between the 2 drugs. This prospective, open-label, noncomparative, multicenter, phase II study enrolled 45 patients (>/=18 years) with stable PAH (idiopathic, familial, or related to corrected congenital systemic-to-pulmonary shunts, drugs, or toxins) and on bosentan treatment for at least 3 months. Patients underwent right heart catheterization to evaluate the acute hemodynamic effects of (a) inhaled nitric oxide (iNO) and (b) a single oral dose of sildenafil (25 mg). Mean pulmonary vascular resistance (PVR) decreased from baseline following iNO (-15%; 95% confidence limits: -21... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2808154 Mon, 14 Sep 2009 23:00:00 +0100 2808154 http://www.medworm.com/index.php?rid=2783132&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19737980%26dopt%3DAbstract The objective of this study was to establish effects of liraglutide on the QTc interval. In this randomized, placebo-controlled, double-blind crossover study, 51 healthy participants were administered placebo, 0.6, 1.2, and 1.8 mg liraglutide once daily for 7 days each. Electrocardiograms were recorded periodically over 24 hours at the end of placebo and highest dosing periods. Four different models for QT correction were used: QTci, as the primary endpoint, and QTciL, QTcF, and QTcB as secondary endpoints. The upper bound of the 1-sided 95% confidence interval for time-matched, baseline-corrected, placebo-subtracted QTc intervals was <10 ms for all 4 correction methods. Moxifloxacin (400 mg) increased QTc intervals by 10.6 toms at 2 hours. There was no concentration-exposure dependency... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2783132 Mon, 07 Sep 2009 23:00:00 +0100 2783132 http://www.medworm.com/index.php?rid=2778790&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19734373%26dopt%3DAbstract Authors: Rohatagi S, Carrothers TJ, Kuwabara-Wagg J, Khariton T Concentration-QT (C-QT) modeling has been conducted for multiple compounds at various stages of development in different therapeutic areas. Data from available single and multiple ascending-dose (SAD/MAD) studies were pooled to construct population C-QT models, with post hoc predictions of concentration from a pharmacokinetic model. All SAD and MAD studies employed a customized robust QTc assessment with time-matched triplicate electrocardiograms and centralized manual QTc reading. Sources of variability were characterized, and the relationship between covariates and model parameters was explored, with a particular emphasis on correction for heart rate and diurnal variation. The results of population prediction of QTc prol... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2778790 Thu, 03 Sep 2009 23:00:00 +0100 2778790 http://www.medworm.com/index.php?rid=2762708&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19723672%26dopt%3DAbstract Authors: Aouam K, Ben Romdhane F, Loussaief C, Salem R, Toumi A, Belhadjali H, Chaabane A, Boughattas NA, Chakroun M A 14-year-old male presents with erythroderma and fever 44 days after carbamazepine intake. Laboratory exams show eosinophilia and elevated liver enzymes, and thoracic imaging reveals interstitial pneumonitis. All symptoms disappear after carbamazepine withdrawal. A patch test to carbamazepine performed 6 weeks after recovery is positive. About 8 months later, the patient exhibits the same clinical and biological picture 52 days after lamotrigine intake. Lamotrigine is stopped and all symptoms disappear. A patch test to LMG is positive. This case illustrates a possible cross-reactivity between carbamazepine and lamotrigine, which are aromatic and nonaromatic anticonvulsa... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2762708 Mon, 31 Aug 2009 23:00:00 +0100 2762708 http://www.medworm.com/index.php?rid=2762707&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19723673%26dopt%3DAbstract Authors: Ma P, Yang BB, Wang YM, Peterson M, Narayanan A, Sutjandra L, Rodriguez R, Chow A Panitumumab is a fully human monoclonal antibody targeted to the extracellular domain of human epidermal growth factor receptor (EGFR). A comprehensive population pharmacokinetic model of panitumumab was developed using nonlinear mixed-effects modeling of 1200 patients with advanced solid tumors in 14 clinical studies. The disposition of panitumumab was best described with a 2-compartment model with parallel linear and nonlinear (Michaelis-Menten) elimination pathways. For a typical male patient with colorectal cancer (80 kg, 60 years old), the estimates for the linear clearance (CL), the maximum nonlinear clearance (Vmax/Km), the central volume of distribution (V1), the peripheral volume of dist... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2762707 Mon, 31 Aug 2009 23:00:00 +0100 2762707 http://www.medworm.com/index.php?rid=2753036&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19717724%26dopt%3DAbstract Authors: Krishna R PMID: 19717724 [PubMed - in process] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2753036 Mon, 31 Aug 2009 23:00:00 +0100 2753036 http://www.medworm.com/index.php?rid=2753035&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19717725%26dopt%3DAbstract Authors: Burmeister Getz E, Fisher DM, Fuller R Pitrakinra, a 15-kDa recombinant human interleukin-4 mutein, targets allergic Th2 inflammation by competitively binding to interleukin-4 receptor alpha to interfere with interleukin-4 and interleukin-13 action. The authors characterized pitrakinra pharmacokinetics using data from 96 atopic patients, then compared pharmacokinetics with pharmacological response in asthma following subcutaneous versus inhalation dosing. A 1-compartment systemic model with site-specific absorption describes pitrakinra pharmacokinetics following subcutaneous, nebulization, and inhalation powder delivery. Typical CL/F and V/F, referenced to subcutaneous administration, are 15.5 L/h and 67.5 L, yielding a 3.0-hour half-life of plasma decline. Absorption into the... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2753035 Mon, 31 Aug 2009 23:00:00 +0100 2753035 http://www.medworm.com/index.php?rid=2753038&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19717722%26dopt%3DAbstract Authors: van Luin M, Colbers A, Verwey-van Wissen CP, van Ewijk-Beneken-Kolmer EW, van der Kolk M, Hoitsma A, da Silva HG, Burger DM The authors studied the effect of raltegravir on the pharmacokinetics of the antiepileptic agent lamotrigine. Twelve healthy volunteers (group A) received 400 mg raltegravir twice daily from days 1 to 5. On day 4, a single dose of 100 mg lamotrigine was administered. After a washout period, participants received a second single dose of 100 mg of lamotrigine but now without raltegravir (day 32). In group B, 12 participants received the same treatment as in group A but in reverse order. On days 4 and 32, 48-hour pharmacokinetic curves were drawn. Geometric mean ratios (+90% confidence intervals [CIs]) of lamotrigine area under the plasma concentration-time ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2753038 Thu, 27 Aug 2009 23:00:00 +0100 2753038 http://www.medworm.com/index.php?rid=2753037&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19717723%26dopt%3DAbstract Authors: Escobar-Chávez JJ, Bonilla-Martí Nez D, Villegas-González MA, Revilla-Vázquez AL Transdermal drug delivery offers an attractive alternative to the conventional drug delivery methods of oral administration and injection. However, the stratum corneum acts as a barrier that limits the penetration of substances through the skin. Application of high-voltage pulses to the skin increases its permeability (electroporation) and enables the delivery of various substances into and through the skin. The application of electroporation to the skin has been shown to increase transdermal drug delivery. Moreover, electroporation, used alone or in combination with other enhancement methods, expands the range of drugs (small to macromolecules, lipophilic or hydrophilic, charg... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2753037 Thu, 27 Aug 2009 23:00:00 +0100 2753037 http://www.medworm.com/index.php?rid=2744452&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19713555%26dopt%3DAbstract Authors: Boom S, Talluri K, Janssens L, Remmerie B, De Meulder M, Rossenu S, van Osselaer N, Eerdekens M, Cleton A Paliperidone extended-release tablet (paliperidone ER) is a centrally active dopamine D2- and serotonergic 5-HT2A-receptor antagonist that is registered for the treatment of schizophrenia. The controlled rate of release of paliperidone from the ER formulation is designed to have a slower absorption rate, which results in gradual ascending plasma concentrations with observed maximum plasma concentrations occurring at 24 hours after dosing on the first dosing day. On subsequent treatment days, the ER formulation provides minimal fluctuations in plasma concentrations. Paliperidone is eliminated with a terminal half-life of approximately 24 hours. Steady state is achieved afte... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2744452 Wed, 26 Aug 2009 23:00:00 +0100 2744452 http://www.medworm.com/index.php?rid=2606321&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19602717%26dopt%3DAbstract Authors: Ameer B, Krivoy N PMID: 19602717 [PubMed - in process] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2606321 Thu, 16 Jul 2009 13:12:16 +0100 2606321 http://www.medworm.com/index.php?rid=2606320&cid=s_32524_13_f&fid=32524&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D19602718%26dopt%3DAbstract This study was a randomized, double-blind, placebo-controlled, group-sequential, dose-escalating design. Forty participants, 10 per dose level (8 receiving TETA, 2 receiving placebo), received twice-daily doses for 14 consecutive days. A 2-compartment model for the PK and a linear direct effect model for drug-induced copper excretion (PD) were employed. The population PK/PD model was applied using the NONMEM software. Covariates tested were glomerular filtration rate (GFR), body weight, and gender. Multiple daily doses of TETA were safe and generally well tolerated. The linear 2-compartment model with first-order absorption well characterized the serum concentration data. Although its role was small, GFR had a statistically significant (P < .05) influence on systemic clearance (CL/F). T... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=2606320 Thu, 16 Jul 2009 13:12:14 +0100 2606320