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. Wed, 08 Feb 2012 14:04:32 +0100 http://www.medworm.com/index.php?rid=5662672&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%3D22300667%26dopt%3DAbstract Authors: Cao J, Song W, Gu B, Mei YN, Tang JP, Meng L, Yang CQ, Wang H, Zhou H Abstract To investigate the correlation between carbapenem consumption and rates of antimicrobial resistance in Acinetobacter baumannii, carbapenem consumption was expressed as defined daily dose based on the World Health Organization (WHO) anatomical therapeutic chemical classification index. Clinical isolates from 2001-2009 were collected and analyzed using WHONET 5.4 software. Results show that the consumption of imipenem/cilastatin, meropenem, and total carbapenem is significantly correlated with imipenem resistance in A baumannii (r = 0.818, P = .007; r = 0.817, P = .007; r = 0.827, P = .006). Furthermore, total carbapenem consumption is significantly correlated with meropenem resistance in A bauman... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5662672 Thu, 02 Feb 2012 05:00:00 +0100 5662672 http://www.medworm.com/index.php?rid=5662674&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%3D22298811%26dopt%3DAbstract Authors: Morey TE, Wasdo S, Wishin J, Quinn B, van der Straten A, Booth M, Gonzalez D, Derendorf H, Melker RJ, Dennis DM Abstract Adherence to microbicide gel use is critical to optimizing effectiveness in preventing human immunodeficiency virus transmission. The authors hypothesized that ester taggants added to vaginal gels would generate exhaled alcohol and ketone metabolites and provide a "breath test" for vaginal gel use. This 2-arm (vaginal and dermal), randomized, participant-blinded, pilot study tested this hypothesis. On 8 visits, healthy women (n = 8) received intravaginal taggant (2-butyl acetate, 2-pentyl acetate, isopropyl butyrate, or 2-pentyl butyrate; 30 mg) formulated in hydroxyethylcellulose or tenofovir placebo gel. A second group (n = 4) of women received the sam... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5662674 Tue, 31 Jan 2012 05:00:00 +0100 5662674 http://www.medworm.com/index.php?rid=5662673&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%3D22298812%26dopt%3DAbstract Authors: Spinler S Abstract Dabigatran etexilate is an oral prodrug of dabigatran, a direct thrombin inhibitor, that provides the first available oral anticoagulant alternative to warfarin for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF). Although warfarin is effective, many patients with AF remain undertreated, primarily because of the management challenges associated with warfarin therapy. Dabigatran etexilate offers several potential advantages over warfarin, including fixed dosing, no requirement for blood coagulation monitoring, and reduced propensity for drug-drug interactions. In a large phase 3 trial in patients with nonvalvular AF, the US Food and Drug Administration (FDA)-approved dose of dabigatran etexilate (150... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5662673 Tue, 31 Jan 2012 05:00:00 +0100 5662673 http://www.medworm.com/index.php?rid=5643694&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%3D22287694%26dopt%3DAbstract Authors: Wang X, Kay A, Anak O, Angevin E, Escudier B, Zhou W, Feng Y, Dugan M, Schran H Abstract Dovitinib is an oral multitargeted kinase inhibitor with potent activity against receptors for vascular endothelial growth factor, platelet-derived growth factor, and basic fibroblast growth factor. Initial phase 1 to 2 studies of dovitinib using a continuous daily dosing schedule has shown that dovitinib exhibits a prolonged and overproportional increase in dose and exposure relationship above 400 mg/d. To address this, intermittent dosing schedules were explored using a model-based approach. A semi-mechanistic population pharmcokinetic/pharmacodynamic (PD) model was developed from 4 dovitinib phase 1 studies with daily dosing schedules. Autoinduction of cytochrome P450 1A (CYP1A) res... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5643694 Fri, 27 Jan 2012 05:00:00 +0100 5643694 http://www.medworm.com/index.php?rid=5643693&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%3D22287695%26dopt%3DAbstract Authors: Nisi A, Panfili M, De Rosa G, Boffa G, Groppa F, Gusella M, Padrini R Abstract Pentoxifylline (PTX) is extensively metabolized in the body, and all its 3 plasma metabolites (M1, M4, M5) are pharmacologically active. The authors evaluated the pharmacokinetics of PTX and its metabolites in 20 patients with chronic heart failure (CHF). Eleven had moderate and 9 severe CHF. The time courses of PTX, M1, M4, and M5 plasma levels were determined after oral administration of a sustained-release 600-mg tablet of PTX, and for each compound, AUC, maximal plasma concentration (C(max)), and time to C(max) (T(peak)) were calculated. Compared with patients with moderate CHF, those with severe CHF showed a significant delay in T(peak) of PTX (3.9 vs 1.6 hours) and M5 (5.6 vs 3.6 hours), a... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5643693 Fri, 27 Jan 2012 05:00:00 +0100 5643693 http://www.medworm.com/index.php?rid=5643696&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%3D22282526%26dopt%3DAbstract In conclusion, a single dose of pasireotide SC 600 µg was well tolerated in subjects with hepatic impairment. Drug exposure in subjects with mild hepatic impairment was similar to that seen in healthy volunteers, whereas subjects with moderate and severe hepatic impairment experienced higher exposure to pasireotide. Adjustment of the pasireotide dose may be required for patients with moderate and severe hepatic impairment. PMID: 22282526 [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=5643696 Thu, 26 Jan 2012 05:00:00 +0100 5643696 http://www.medworm.com/index.php?rid=5643695&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%3D22282527%26dopt%3DAbstract Authors: Kim JW, Yi S, Kim TE, Lim KS, Yoon SH, Cho JY, Lee MG, Song IS, Shin SG, Jang IJ, Yu KS Abstract The authors studied the effects of ketoconazole and rifampicin on the pharmacokinetics of a single dose of fimasartan (BR-A-657), a newly developed angiotensin II receptor antagonist for the treatment of hypertension, in 22 healthy participants. Ketoconazole increased the maximum plasma concentration (C(max)) and area under the plasma concentration vs time curve to infinity (AUC(∞)) of fimasartan by 2.47-fold (90% confidence interval [CI], 1.61-3.79) and 2.03-fold (1.56-2.64), respectively. Concomitant administration of rifampicin increased the C(max) and AUC(∞) of fimasartan by 10.33-fold (90% CI, 6.74-15.81) and 4.60-fold (3.54-5.97). In vitro studies indicated that ketoc... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5643695 Thu, 26 Jan 2012 05:00:00 +0100 5643695 http://www.medworm.com/index.php?rid=5643697&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%3D22275382%26dopt%3DAbstract In this study, the authors compared the effects of amlodipine (AML) on the bioavailability of cephalexin (LEX) and cefuroxime axetil (CXM). Twenty-four healthy men were randomized to 4 treatments according to a crossover design with a 14-day washout. After an overnight fast, they were administered orally LEX 500 mg alone, LEX 500 mg 2 hours after oral administration of AML 5 mg, CXM 500 mg alone, and CXM 500 mg 2 hours after oral administration of AML 5 mg. All participants completed the whole study without side effects being observed. Pharmacokinetic data were analyzed by noncompartmental modeling with WinNonlin software. The geometric mean (GM) ratios were 1.38 (90% confidence interval [CI], 1.32-1.45) for the area under the concentration-time curve (AUC) for LEX and 1.27 (1.18-1.36) for... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5643697 Tue, 24 Jan 2012 05:00:00 +0100 5643697 http://www.medworm.com/index.php?rid=5625961&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%3D22261414%26dopt%3DAbstract This study determined the pharmacokinetics (PK) of figitumumab and its effects on insulin-like growth factor (IGF) axis-related biomarkers, following a single intravenous dose (10 [n = 16] and 20 [n = 12] mg/kg) in healthy adults. Serial blood sampling for PK and biomarkers was conducted up to 84 days postdose. A dose increase from 10 to 20 mg/kg led to 1.9- and 2.4-fold increases in mean C(max) and AUC(∞), respectively. Median disposition half-life was 21.1 and 27.8 days at 10 and 20 mg/kg, respectively. At 10 and 20 mg/kg, figitumumab increased total IGF-1, free IGF-1, IGF binding protein (IGFBP)-3, and insulin by 4.1- and 4.8-, 8.3- and 12.1-, 2.4- and 2.9-, and 7.3- and 9.8-fold, respectively; increases were sustained throughout the 84-day period. There was a slight and transient ele... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5625961 Wed, 18 Jan 2012 05:00:00 +0100 5625961 http://www.medworm.com/index.php?rid=5625960&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%3D22261415%26dopt%3DAbstract Authors: Du W, Tutag Lehr V, Lieh-Lai M, Koo W, Ward RM, Rieder MJ, Van Den Anker JN, Reeves JH, Mathew M, Lulic-Botica M, Aranda JV Abstract Critically ill newborns in neonatal intensive care units (NICUs) are at greater risk of developing adverse drug reactions (ADRs). Differentiation of ADRs from reactions associated with organ dysfunction/immaturity is difficult. Current ADR algorithm scoring was established arbitrarily without validation in infants. The study objective was to develop a valid and reliable algorithm to identify ADRs in the NICU. Algorithm development began with a 24-item questionnaire for data collection on 100 previously suspected ADRs. Five pediatric pharmacologists independently rated cases as definite, probable, possible, and unlikely ADRs. Consensus "gold s... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5625960 Wed, 18 Jan 2012 05:00:00 +0100 5625960 http://www.medworm.com/index.php?rid=5605855&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%3D22245658%26dopt%3DAbstract Authors: Choi CI, Bae JW, Jang CG, Lee SY PMID: 22245658 [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=5605855 Thu, 12 Jan 2012 05:00:00 +0100 5605855 http://www.medworm.com/index.php?rid=5580027&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%3D22235139%26dopt%3DAbstract The objective was to characterize its disposition in patients with renal impairment. A single oral dose of 200 mg brivaracetam was administered to 9 patients with severe renal impairment not requiring dialysis (creatinine clearance <15 mL/min, n = 6; 15-29 mL/min, n = 3) and 9 matched healthy controls. Plasma and urinary concentrations of brivaracetam and 3 pharmacologically inactive metabolites (acid, hydroxy, and hydroxyacid) were determined up to 72 hours postdose, and noncompartmental pharmacokinetic parameters were derived. The C(max) of brivaracetam was unchanged relative to healthy controls, whereas AUC was slightly increased (mean ratio, 1.21; 90% confidence interval, 1.01-1.45). Nonrenal and renal clearances of brivaracetam decreased from 47 and 4.5 to 41 and 1.7 mL/min/1.73 m(... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5580027 Tue, 10 Jan 2012 05:00:00 +0100 5580027 http://www.medworm.com/index.php?rid=5580026&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%3D22235140%26dopt%3DAbstract Authors: Li J, Zhi J, Wenger M, Valente N, Dmoszynska A, Robak T, Mangat R, Joshi A, Visich J Abstract This retrospective analysis characterizes rituximab population pharmacokinetics in combination with fludarabine and cyclophosphamide and its effect on fludarabine and cyclophosphamide disposition in chronic lymphocytic leukemia (CLL) patients. Rituximab concentration data were well described by a 2-compartment model comprising a time-varying clearance component related to the target-mediated clearance pathway and a constant clearance component reflecting catabolic elimination pathway. Marked differences were observed compared to pharmacokinetic parameters for non-Hodgkin lymphoma (NHL) obtained previously: in CLL, time-varying clearance at time zero (CL(2)) was faster, volumes of ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5580026 Tue, 10 Jan 2012 05:00:00 +0100 5580026 http://www.medworm.com/index.php?rid=5580030&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%3D22232731%26dopt%3DAbstract Authors: Shacham-Shmueli E, Geva R, Figer A, Bulocinic S, Nalbandyan K, Shpigel S, Atsmon J, Brendel E Abstract This dose escalation, uncontrolled phase I study evaluated the tolerability, pharmacokinetics (PK), and antitumor activity of oral sorafenib 100, 200, or 400 mg twice daily (bid, continuous regimen) in combination with 5-fluorouracil/leucovorin (5-FU/LCV, intravenous infusion or bolus) in patients with advanced, solid tumors. A total of 47 patients (median age 57 years; colon cancer, 55%; pancreatic cancer, 21%; prior systemic therapy, 96%) received treatment; 24 were included in the PK analyses, and 38 were evaluable for tumor response. Treatment-emergent adverse events were observed in 98% of patients (≥grade 3, 55%); the most frequently reported were fatigue (51%), s... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5580030 Mon, 09 Jan 2012 05:00:00 +0100 5580030 http://www.medworm.com/index.php?rid=5580029&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%3D22232732%26dopt%3DAbstract In this study, the authors investigated the response to clopidogrel in Iranian patients after PCI. Patients who were candidates for elective PCI were enrolled in this study. All patients had received aspirin 80 to 325 mg daily for ≥1 week before PCI. Blood samples were taken from patients at baseline, 2 hours after taking a 600-mg loading dose of clopidogrel, and 24 hours and 30 days after stenting. Platelet aggregation was measured by light transmittance aggregometry with adenosine diphosphate (5 and 20 μM) and arachidonic acid (500 and 5000 μg/mL). One hundred twelve patients were included (79 men, 33 women). Maximal and minimal clopidogrel nonresponsiveness occurred at 2 hours (26%) and 48 hours (13%) after taking 600 mg clopidogrel, respectively. Pretreatment platelet reactivity ha... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5580029 Mon, 09 Jan 2012 05:00:00 +0100 5580029 http://www.medworm.com/index.php?rid=5580028&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%3D22232733%26dopt%3DAbstract In conclusion, serum imiquimod concentrations were low after daily self-application to external anogenital warts of up to 1 packet of imiquimod 3.75% cream for 21 days. PMID: 22232733 [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=5580028 Mon, 09 Jan 2012 05:00:00 +0100 5580028 http://www.medworm.com/index.php?rid=5566869&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%3D22207766%26dopt%3DAbstract Authors: Musuamba FT, Mourad M, Haufroid V, Demeyer M, Capron A, Delattre IK, Delaruelle F, Wallemacq P, Verbeeck RK Abstract Mycophenolic acid (MPA) and tacrolimus (TAC) are immunosuppressive agents used in combination with corticosteroids for the prevention of acute rejection after solid organ transplantation. Their pharmacokinetics (PK) show considerable unexplained intraindividual and interindividual variability, particularly in the early period after transplantation. The main objective of the present work was to design a study based on D-optimality to describe the PK of the 2 drugs with good precision and accuracy and to explain their variability by means of patients' demographics, biochemical test results, and physiological characteristics. Pharmacokinetic profiles of MPA and... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5566869 Thu, 29 Dec 2011 05:00:00 +0100 5566869 http://www.medworm.com/index.php?rid=5552279&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%3D22205719%26dopt%3DAbstract Authors: Venitz J, Zack J, Gillies H, Allard M, Regnault J, Dufton C Abstract The authors review the basic pharmacology and potential for adverse drug-drug interactions (DDIs) of bosentan and ambrisentan, the 2 endothelin receptor antagonists currently approved for pulmonary arterial hypertension (PAH) treatment. Bosentan, an endothelin (ET) receptor-type ET(A) and ET(B) antagonist, is metabolized to active metabolites by and an inducer of cytochrome P450 (CYP)2C9 and CYP3A. Ambrisentan, a selective ET(A) receptor antagonist, is metabolized primarily by uridine 5'diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S and, to a lesser extent, by CYP3A and CYP2C19. Drug interactions observed with bosentan DDI studies have demonstrated a potential for significant clinical im... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5552279 Wed, 28 Dec 2011 05:00:00 +0100 5552279 http://www.medworm.com/index.php?rid=5537726&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%3D22187440%26dopt%3DAbstract Authors: George S, Rodriguez I, Ipe D, Sager PT, Gussak I, Vajdic B Abstract Continuous Holter recordings are often used in thorough QT studies (TQTS), with multiple 10-second electrocardiograms (ECGs) visually selected around predesignated time points. The authors hypothesized that computer-automated ECG selection would reduce within-subject variability, improve study data precision, and increase study power. Using the moxifloxacin and placebo arms of a Holter-based crossover TQTS, the authors compared interval duration measurements (IDMs) from manually selected to computer-selected ECGs. All IDMs were made with a fully automated computer algorithm. Moxifloxacin-induced changes in baseline- and placebo-subtracted QT intervals were similar for manual and computer ECG selection. Mea... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537726 Tue, 20 Dec 2011 05:00:00 +0100 5537726 http://www.medworm.com/index.php?rid=5537727&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%3D22180560%26dopt%3DAbstract Authors: Tremoulet AH, Nikanjam M, Cressey TR, Chokephaibulkit K, McKinney R, Mirochnick M, Capparelli EV Abstract Lamivudine is a nucleoside reverse transcriptase inhibitor widely used in infants and children in combination antiretroviral therapy to treat human immunodeficiency virus (HIV) infection. Developmental changes in lamivudine pharmacokinetic disposition were assessed by combining data from 7 studies of lamivudine (Pediatric AIDS Clinical Trials Group 300, 353, 356, 358, 386, 1056, and 1069) representing subjects across the pediatric age continuum. A population pharmacokinetic model was developed to identify factors that influence lamivudine disposition. Age and Thai race were independent predictors of apparent clearance (CL/F), whereas the use of a fixed drug combination... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537727 Fri, 16 Dec 2011 05:00:00 +0100 5537727 http://www.medworm.com/index.php?rid=5537740&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%3D22174426%26dopt%3DAbstract In conclusion, these results do not suggest an increased risk of retinoid embryopathy. However, according to current knowledge, topical retinoids cannot be advised for use during pregnancy because their risk/benefit ratio remains questionable. PMID: 22174426 [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=5537740 Thu, 15 Dec 2011 05:00:00 +0100 5537740 http://www.medworm.com/index.php?rid=5537739&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%3D22174427%26dopt%3DAbstract Authors: Mehrotra S, Florian J, Gobburu J PMID: 22174427 [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=5537739 Thu, 15 Dec 2011 05:00:00 +0100 5537739 http://www.medworm.com/index.php?rid=5537738&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%3D22174428%26dopt%3DAbstract This article provides insights into the use of pharmacometric analyses for regulatory review with a focus on the dosing recommendations. The assessment was based on the totality of exploratory and confirmatory analysis of dose-finding and pivotal clinical data and was structured around a set of key questions in accordance with current FDA review practice. For the pharmacometric review of liraglutide, the key questions focused on exposure-response relationships for effects on fasting plasma glucose, hemoglobin A(1c), and calcitonin and on variability in exposure across demographic subgroups of patients. The importance of conducting exploratory exposure-response analysis and population pharmacokinetic studies in clinical drug development to support dosing recommendations is highlighted. ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537738 Thu, 15 Dec 2011 05:00:00 +0100 5537738 http://www.medworm.com/index.php?rid=5537737&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%3D22174429%26dopt%3DAbstract Authors: Boulton C, Meiser K, David OJ, Schmouder R Abstract Fingolimod, a first-in-class oral sphingosine 1-phosphate receptor (S1PR) modulator, is approved in many countries for relapsing-remitting multiple sclerosis, at a once-daily 0.5-mg dose. A reduction in peripheral lymphocyte count is an expected consequence of the fingolimod mechanism of S1PR modulation. The authors investigated if this pharmacodynamic effect impacts humoral and cellular immunogenicity. In this double-blind, parallel-group, 4-week study, 72 healthy volunteers were randomized to steady state, fingolimod 0.5 mg, 1.25 mg, or to placebo. The authors compared T-cell dependent and independent responses to the neoantigens, keyhole limpet hemocyanin (KLH), and pneumococcal polysaccharides vaccine (PPV-23), respec... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537737 Thu, 15 Dec 2011 05:00:00 +0100 5537737 http://www.medworm.com/index.php?rid=5537736&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%3D22174430%26dopt%3DAbstract Authors: Jauslin PM, Karlsson MO, Frey N Abstract A mechanistic drug-disease model was developed on the basis of a previously published integrated glucose-insulin model by Jauslin et al. A glucokinase activator was used as a test compound to evaluate the model's ability to identify a drug's mechanism of action and estimate its effects on glucose and insulin profiles following oral glucose tolerance tests. A kinetic-pharmacodynamic approach was chosen to describe the drug's pharmacodynamic effects in a dose-response-time model. Four possible mechanisms of action of antidiabetic drugs were evaluated, and the corresponding affected model parameters were identified: insulin secretion, glucose production, insulin effect on glucose elimination, and insulin-independent glucose elimination... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537736 Thu, 15 Dec 2011 05:00:00 +0100 5537736 http://www.medworm.com/index.php?rid=5537735&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%3D22174431%26dopt%3DAbstract In conclusion, aliskiren 150 and 300 mg provided effective blood pressure control in elderly patients when given with a light meal. PMID: 22174431 [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=5537735 Thu, 15 Dec 2011 05:00:00 +0100 5537735 http://www.medworm.com/index.php?rid=5537734&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%3D22174432%26dopt%3DAbstract Authors: Mulla H, Leary A, White P, Pandya HC PMID: 22174432 [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=5537734 Thu, 15 Dec 2011 05:00:00 +0100 5537734 http://www.medworm.com/index.php?rid=5537733&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%3D22174433%26dopt%3DAbstract Authors: Bou Akl I, Ghaddar F, Sabra R, Parmelee D, Simaan JA, Kanafani ZA, Zgheib NK Abstract The purpose of this study was to formulate evidence-based recommendations on whether to deliver the team-based learning (TBL)-designed clinical pharmacology course at the American University of Beirut Faculty of Medicine (AUBFM) during the third year instead of the fourth and final year of the medical curriculum. Between June 2010 and May 2011, AUBFM offered the course to both classes simultaneously to compare their performance. The findings of this endeavor supported the introduction of the course during the third year, first because fourth-year students did not outperform third-year students despite having the advantage of an additional year of clinical experience, and second, third-yea... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537733 Thu, 15 Dec 2011 05:00:00 +0100 5537733 http://www.medworm.com/index.php?rid=5537732&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%3D22174434%26dopt%3DAbstract In conclusion, AI treatment and/or washout of tamoxifen induced detrimental changes in the lipid profile of postmenopausal women with breast cancer. PMID: 22174434 [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=5537732 Thu, 15 Dec 2011 05:00:00 +0100 5537732 http://www.medworm.com/index.php?rid=5537731&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%3D22174435%26dopt%3DAbstract This study developed a population pharmacokinetic model of MPA in HCT recipients and created limited sampling schedules (LSSs) to enable individualized pharmacotherapy. A retrospective evaluation of MPA concentration-time data following a 2-hour MMF intravenous (IV) infusion was conducted in 77 HCT recipients. The final model consisted of 1 and 2 compartments for MMF and MPA pharmacokinetics, respectively. The mean estimated values (coefficient of variation, %) for total systemic clearance, distributional clearance, and central and peripheral compartment volumes of MPA were 36.9 L/h (34.5%), 15.3 L/h (80.4%), 11.9 L (71.7%), and 182 L (127%), respectively. No covariates significantly explained variability among individuals. Optimal LSSs were derived using a simulation approach based on the... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537731 Wed, 14 Dec 2011 05:00:00 +0100 5537731 http://www.medworm.com/index.php?rid=5537730&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%3D22174436%26dopt%3DAbstract Authors: Cirillo I, Vaccaro N, Redman R, Black PL, Kearns GL Abstract The pharmacokinetics of doripenem and doripenem-M-1 (inactive metabolite) were evaluated in an open-label, 2-period, single-sequence study in which single 1-g and 2-g doses of doripenem were administered intravenously over 4 hours to adult patients with cystic fibrosis (CF). The systemic exposure to doripenem and doripenem-M-1, as measured by observed apparent maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC), increased approximately proportionally to the increase in dose. Other pharmacokinetic parameters of doripenem and doripenem-M-1, including clearance, volume of distribution, and elimination half-life, were similar for the 1-g and 2-g doses. The results from this ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537730 Wed, 14 Dec 2011 05:00:00 +0100 5537730 http://www.medworm.com/index.php?rid=5537729&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%3D22174437%26dopt%3DAbstract Authors: Aquilante CL, Kiser JJ, Anderson PL, Christians U, Kosmiski LA, Daily EB, Hoffman KL, Hopley CW, Predhomme JA, Schniedewind B, Sidhom MS Abstract The authors investigated whether SLCO1B1 polymorphisms contribute to variability in pravastatin pharmacokinetics when pravastatin is administered alone versus with darunavir/ritonavir. HIV-negative healthy participants were prospectively enrolled on the basis of SLCO1B1 diplotype: group 1 (*1A/*1A, n = 9); group 2 (*1A/*1B, n = 10; or *1B/*1B, n = 2); and group 3 (*1A/*15, n = 1; *1B/*15, n = 5; or *1B/*17, n = 1). Participants received pravastatin (40 mg) daily on days 1 through 4, washout on days 5 through 11, darunavir/ritonavir (600/100 mg) twice daily on days 12 through 18, with pravastatin 40 mg added back on days 15 throug... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537729 Wed, 14 Dec 2011 05:00:00 +0100 5537729 http://www.medworm.com/index.php?rid=5537728&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%3D22174438%26dopt%3DAbstract Authors: Yiannakopoulou E Abstract Recent studies have implicated that lymphangiogenesis plays a role in the development of metastasis in experimental cancer models and in certain types of human tumors. Epidemiological and laboratory data suggest that non steroidal anti-inflammatory agents (NSAIDs) have antitumor activities, although the mechanisms have not been elucidated. This systematic review aimed to synthesize data on the effect of aspirin and other NSAIDs on lymphangiogenesis. In particular, an answer was attempted to be found for the following primary questions: Is there an effect of aspirin and NSAIDs on lymphangiogenesis? If yes, is this effect mediated through COX-II inhibition or through COX-II-independent mechanisms? Electronical databases were searched with the approp... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537728 Wed, 14 Dec 2011 05:00:00 +0100 5537728 http://www.medworm.com/index.php?rid=5537750&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%3D22167563%26dopt%3DAbstract Authors: Perez-Ruixo JJ, Green B, Doshi S, Wang YM, Mould DR Abstract A pharmacodynamic model was developed for platelet counts in 52 patients with immune thrombocytopenia (ITP) receiving subcutaneous romiplostim in 3 phase I/II studies (dose range, 0.2-10 µg/kg). The model consisted of a drug-sensitive progenitor cell compartment linked to a peripheral blood compartment through 4 transition compartments. The baseline platelet count, mean transit time, and kinetics of drug effect constant were 11.1 × 10(9)/L, 170 hours, and 0.6 day(-1), respectively. The ITP patients had a shorter platelet life span and lower progenitor cell production rates than healthy volunteers. Romiplostim response was described for 2 subpopulations. The romiplostim stimulatory effect in ITP patients was 351... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537750 Tue, 13 Dec 2011 05:00:00 +0100 5537750 http://www.medworm.com/index.php?rid=5537749&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%3D22167564%26dopt%3DAbstract Authors: Lloyd P, Zhou H, Theil FP, Kakkar T, Nestorov I, Roberts SA PMID: 22167564 [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=5537749 Tue, 13 Dec 2011 05:00:00 +0100 5537749 http://www.medworm.com/index.php?rid=5537748&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%3D22167565%26dopt%3DAbstract Authors: Williams JH, Jayaraman B, Swoboda KJ, Barrett JS Abstract Valproic acid (VPA) dosing strategies used in recent clinical trials in patients with spinal muscular atrophy (SMA) have utilized a paradigm of monitoring trough levels to estimate drug exposure with subsequent dose titration. The validity of this approach remains uncertain and could be improved by understanding sources of pharmacokinetic variability. A population pharmacokinetic analysis of VPA in pediatric patients with epilepsy was recently performed. The pooled data set included 52 subjects with epilepsy, ages 1 to 17 years, who received intravenous and/or various oral formulations. The data was best fit by a 2-compartment model; inclusion of age and weight reduced intersubject variability for clearance (41%), c... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537748 Tue, 13 Dec 2011 05:00:00 +0100 5537748 http://www.medworm.com/index.php?rid=5537747&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%3D22167566%26dopt%3DAbstract Authors: Cutler DL, Tendolkar A, Grachev ID Abstract The aim of this study was to evaluate the effect of food on the oral bioavailability of preladenant, a novel adenosine A(2A) receptor antagonist. This open-label, randomized, single-dose, 2-way crossover study evaluated the effects of a high-fat, high-calorie meal on the pharmacokinetics of preladenant and its metabolite (SCH434748) following oral administration of a single 25-mg preladenant capsule to 24 healthy subjects. When administered with food, the time of maximum concentration (T(max)) of preladenant was prolonged compared with administration in the fasting state. Whereas T(max) was increased from 0.9 hours to 2.6 hours and maximum concentration (C(max)) was decreased (from 212 ng/mL to 128 ng/mL), the extent of absorptio... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537747 Tue, 13 Dec 2011 05:00:00 +0100 5537747 http://www.medworm.com/index.php?rid=5537746&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%3D22167567%26dopt%3DAbstract Authors: Levinson P, Glaumann H, Söderberg M PMID: 22167567 [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=5537746 Tue, 13 Dec 2011 05:00:00 +0100 5537746 http://www.medworm.com/index.php?rid=5537745&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%3D22167568%26dopt%3DAbstract Authors: Wang DD PMID: 22167568 [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=5537745 Tue, 13 Dec 2011 05:00:00 +0100 5537745 http://www.medworm.com/index.php?rid=5537744&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%3D22167569%26dopt%3DAbstract Authors: Lowry E, Woodman RJ, Soiza RL, Hilmer SN, Mangoni AA Abstract The Drug Burden Index (DBI) is associated with poorer physical function in stable, community-dwelling, older people. The authors speculated that a higher DBI is associated with reduced physical function (Barthel Index, primary outcome) and predicts adverse outcomes (length of stay, in-hospital mortality, secondary outcomes) in frail, acutely ill, older hospitalized patients. Clinical and demographic characteristics, Barthel Index, DBI, and full medication exposure were recorded on admission in 362 consecutive patients (84 ± 7 years old) admitted to 2 acute geriatric units between February 1, 2010, and June 30, 2010. A unit increase in DBI was associated with a 29% reduction in the odds of being in a higher Bart... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537744 Tue, 13 Dec 2011 05:00:00 +0100 5537744 http://www.medworm.com/index.php?rid=5537743&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%3D22167570%26dopt%3DAbstract Authors: Degorter MK, Urquhart BL, Gradhand U, Tirona RG, Kim RB Abstract Response to statin therapy is often unpredictable because of variability in metabolism and transport. In the recently created organic anion transporting-polypeptide 1b2 (Oatp1b2/Slco1b2)-null mice, the investigators found significantly lower liver-to-plasma ratios compared with controls for atorvastatin (16.0 ± 5.1 vs 43.5 ± 13.7, P = .002) and rosuvastatin (15.2 ± 3.3 vs 28.4 ± 9.3, P = .03), but not simvastatin (5.2 ± 1.1 vs 6.3 ± 2.9, P = .49), following tail vein injection of 1 mg/kg of each drug. In addition, the investigators examined intraindividual variation in atorvastatin, rosuvastatin, and simvastatin pharmacokinetics in healthy human subjects in a crossover study design. Areas under the plas... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537743 Tue, 13 Dec 2011 05:00:00 +0100 5537743 http://www.medworm.com/index.php?rid=5537742&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%3D22167571%26dopt%3DAbstract Authors: Skarke C, Kuczka K, Tausch L, Werz O, Rossmanith T, Barrett JS, Harder S, Holtmeier W, Schwarz JA PMID: 22167571 [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=5537742 Tue, 13 Dec 2011 05:00:00 +0100 5537742 http://www.medworm.com/index.php?rid=5537741&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%3D22167572%26dopt%3DAbstract Authors: Buccelletti F, Iacomini P, Botta G, Marsiliani D, Carroccia A, Gentiloni Silveri N, Franceschi F Abstract Vernakalant is an emergent antiarrhythmic drug that, in preclinical studies, has demonstrated high efficacy in restoring sinus rhythm and safety in patients with rapid recent-onset atrial fibrillation. The aim of this work was to evaluate the efficacy and safety of vernakalant for cardioversion of recent-onset atrial fibrillation. PubMed, EMBASE, Clinical Trials Registry, and European Medicines Agency public reports were searched for randomized clinical trials, until May 2011, of vernakalant compared with controls (placebo/other antiarrhythmic drug) in enrolled patients with high ventricular rate atrial fibrillation. Five randomized trials that met inclusion criteria e... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537741 Tue, 13 Dec 2011 05:00:00 +0100 5537741 http://www.medworm.com/index.php?rid=5537760&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%3D22162533%26dopt%3DAbstract Authors: Knebel W, Rao N, Uchimura T, Mori A, Fisher J, Gastonguay MR, Chaikin P Abstract This model-based analysis quantifies the population pharmacokinetic-pharmacodynamic efficacy and safety/tolerability relationships of orally administered istradefylline, a selective adenosine A(2A) receptor antagonist, in healthy participants and patients with Parkinson disease. Data from 6 phase 2/3 clinical trials comprised the population database, with 1760 and 1798 patients contributing to the efficacy and safety/tolerability analyses, respectively. The relationship between istradefylline area under the curve at steady state and percentage OFF time was described by a nonlinear model (Emax) based on time for the disease progression/placebo response component and an Emax model for the effect... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537760 Mon, 12 Dec 2011 05:00:00 +0100 5537760 http://www.medworm.com/index.php?rid=5537759&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%3D22162534%26dopt%3DAbstract Authors: Nathan PJ, Bush MA, Tao WX, Koch A, Davies KM, Maltby K, O'Neill BV, Napolitano A, Skeggs AL, Brooke AC, Richards DB, Williams PM, Bullmore ET Abstract The endogenous opioid system and µ-opioid receptors in particular have been demonstrated to play a fundamental role in hedonic and motivational behaviors reinforced by rewards. In healthy participants, the authors examined the multiple-dose safety, pharmacokinetic, and secondary pharmacodynamic profile of GSK1521498, a µ-opioid receptor inverse agonist that is being developed for treatment of disorders of compulsive consumption. Clinically relevant doses of GSK1521498 (2, 5, and 10 mg) following once-daily administration for 10 days, were well tolerated with no clinically relevant changes in vital signs, chemistry, or hem... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537759 Mon, 12 Dec 2011 05:00:00 +0100 5537759 http://www.medworm.com/index.php?rid=5537758&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%3D22162535%26dopt%3DAbstract This study demonstrates that in individuals with mild hepatic impairment, individual dose adaptation may not be required. PMID: 22162535 [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=5537758 Mon, 12 Dec 2011 05:00:00 +0100 5537758 http://www.medworm.com/index.php?rid=5537757&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%3D22162536%26dopt%3DAbstract Authors: Lee MC, Su CP, Wang CH, Lan CC, Wu TW PMID: 22162536 [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=5537757 Mon, 12 Dec 2011 05:00:00 +0100 5537757 http://www.medworm.com/index.php?rid=5537756&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%3D22162537%26dopt%3DAbstract Authors: Wang Y, Jadhav PR, Lala M, Gobburu JV PMID: 22162537 [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=5537756 Mon, 12 Dec 2011 05:00:00 +0100 5537756 http://www.medworm.com/index.php?rid=5537755&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%3D22162538%26dopt%3DAbstract Authors: Yan X, Lowe PJ, Fink M, Berghout A, Balser S, Krzyzanski W Abstract The aim of this study was to develop an integrated pharmacokinetic and pharmacodynamic (PK/PD) model and assess the comparability between epoetin alfa HEXAL/Binocrit (HX575) and a comparator epoetin alfa by a model-based approach. PK/PD data-including serum drug concentrations, reticulocyte counts, red blood cells, and hemoglobin levels-were obtained from 2 clinical studies. In sum, 149 healthy men received multiple intravenous or subcutaneous doses of HX575 (100 IU/kg) and the comparator 3 times a week for 4 weeks. A population model based on pharmacodynamics-mediated drug disposition and cell maturation processes was used to characterize the PK/PD data for the 2 drugs. Simulations showed that due to targ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537755 Mon, 12 Dec 2011 05:00:00 +0100 5537755 http://www.medworm.com/index.php?rid=5537754&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%3D22162539%26dopt%3DAbstract The objective of this model-based meta-analysis was to describe the time course of HbA1c response after dosing with alogliptin (ALOG), saxagliptin (SAXA), sitagliptin (SITA), or vildagliptin (VILD). Publicly available data involving late-stage or marketed DPP-4 inhibitors were leveraged for the analysis. Nonlinear mixed-effects modeling was performed to describe the relationship between DPP-4 inhibition and mean response over time. Plots of the relationship between metrics of DPP-4 inhibition (ie, weighted average inhibition [WAI], time above 80% inhibition, and trough inhibition) and response after 12 weeks of daily dosing were evaluated. The WAI was most closely related to outcome, although other metrics performed well. A model was constructed that included fixed effects for placebo and ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537754 Mon, 12 Dec 2011 05:00:00 +0100 5537754 http://www.medworm.com/index.php?rid=5537753&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%3D22162540%26dopt%3DAbstract This study aimed to investigate a food effect on the bioavailability of modified-release (MR) trimetazidine tablets in 36 healthy volunteers. Trimetazidine, an anti-ischemic drug, protects the myocardial cell from the harmful effects of ischemia. The authors investigated the effect of being under a fasting or fed state at the time of drug intake on the bioavailability of trimetazidine 35-mg MR tablets in a randomized, open-label, crossover, 2-arm, 4-period, 2-sequence bioequivalence study design with a 14-day washout period. Plasma concentration of trimetazidine was assayed in timed samples with a validated high-performance liquid chromatography/mass selective detector that had a lower limit of quantification of 2.5 ng/mL. Test and reference formulations gave a mean trimetazidine C(max) of... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537753 Mon, 12 Dec 2011 05:00:00 +0100 5537753 http://www.medworm.com/index.php?rid=5537752&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%3D22162541%26dopt%3DAbstract We report the safety, tolerability, pharmacokinetics, and pharmacodynamics of oral doses of MK-5046 (10-160 mg) in a double-blind, randomized, placebo-controlled study in healthy and obese male volunteers. MK-5046 exposure increased dose proportionally, and MK-5046 was eliminated with an apparent terminal half-life of 1.5 to 3.5 hours. Single doses transiently increased blood pressure. Patients reported adverse events (erections and feeling hot, cold, and/or jittery) that coincided with time of occurrence (T(max)) and increased with increasing dose. No changes were observed in body temperature, heart rate, plasma glucose levels, or feelings of hunger/satiety. The blood pressure and thermal experiences attenuated with a second dose 6 hours after the first. Additionally, the erections sugges... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537752 Mon, 12 Dec 2011 05:00:00 +0100 5537752 http://www.medworm.com/index.php?rid=5537751&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%3D22162542%26dopt%3DAbstract Authors: Garg V, Chandorkar G, Farmer HF, Smith F, Alves K, van Heeswijk RP Abstract In this open-label study, 24 healthy volunteers received a single intravenous (IV) dose of 0.5 mg of midazolam on day 1 and a single oral dose each of 2 mg of midazolam and 0.5 mg of digoxin on day 3. Telaprevir 750 mg every 8 hours was administered from day 8 through day 23, along with a single IV dose of 0.5 mg of midazolam on day 17 and single oral doses of 2 mg of midazolam and 0.5 mg of digoxin on day 19. Midazolam, 1'-hydroxymidazolam, digoxin, and telaprevir concentrations in plasma and digoxin concentrations in urine were measured and pharmacokinetic parameters calculated. On comparing administration with versus without telaprevir, the geometric least squares mean ratios (with 90% confidenc... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537751 Mon, 12 Dec 2011 05:00:00 +0100 5537751 http://www.medworm.com/index.php?rid=5537761&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%3D22162508%26dopt%3DAbstract Authors: Cawello W, Bonn R Abstract Two open-label, randomized, multiple-dose clinical studies evaluated the potential for pharmacokinetic interaction between the antiepileptic drugs lacosamide and valproic acid. The influence of lacosamide on valproic acid pharmacokinetics (trial A) and valproic acid on lacosamide pharmacokinetics (trial B) was investigated in 32 healthy male volunteers, 16 in each trial. Volunteers in trial A received valproic acid (300 mg bid) with randomization to either early or late addition of lacosamide (200 mg bid). Those in trial B received lacosamide (200 mg bid) with randomization to either early or late addition of valproic acid (300 mg bid). Area under the concentration-time curve during a 12-hour dosing interval at steady state (AUC(τ,ss)) and maxim... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537761 Thu, 08 Dec 2011 05:00:00 +0100 5537761 http://www.medworm.com/index.php?rid=5537762&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%3D22135052%26dopt%3DAbstract Authors: Zhou H, Tsukamoto Y, Davis HM PMID: 22135052 [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=5537762 Thu, 01 Dec 2011 05:00:00 +0100 5537762 http://www.medworm.com/index.php?rid=5460363&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%3D22128200%26dopt%3DAbstract Authors: Klipping C, Duijkers I, Remmers A, Faustmann T, Zurth C, Klein S, Schuett B Abstract Dienogest offers pharmacological advantages for the effective treatment of endometriosis and for use in contraception and hormone replacement therapy. This pharmacodynamic study investigated the ovulation-inhibiting effects of dienogest monotherapy in healthy women. Dienogest was administered at 0.5, 1, 2, or 3 mg daily for up to 72 days to women aged 18 to 35 years (n = 102). Ovarian activity was assessed pretreatment and during 2 treatment periods (days 0-36 and days 37-72) by the Hoogland score, based on follicle size and serum estradiol and progesterone levels. Additional hormonal parameters and endometrial thickness were assessed. Hoogland scoring indicated ovulation in all women pret... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5460363 Tue, 29 Nov 2011 05:00:00 +0100 5460363 http://www.medworm.com/index.php?rid=5460362&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%3D22128201%26dopt%3DAbstract Authors: Hurbin F, Boulenc X, Daskalakis N, Farenc C, Taylor T, Bonneau D, Lacreta F, Cheng S, Sultan E Abstract Clopidogrel requires CYP450-mediated hepatic metabolism to form its active metabolite (clopi-H4). This randomized, placebo-controlled, crossover study was designed to characterize the effect of a high-fat or standard breakfast on adenosine diphosphate (ADP)-induced platelet aggregation and exposure to unchanged clopidogrel and clopi-H4 following clopidogrel (300-mg loading dose, 75 mg/d for 4 days) in 72 healthy men. At day 5 and as assessed by liquid chromatography-tandem mass spectrometry, unchanged clopidogrel area under the concentration-time curve from 0 to 24 hours (AUC(0-24)) increased 3.32-fold (90% confidence interval [CI], 2.88-3.84), and clopi-H4 AUC(0-24) dec... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5460362 Tue, 29 Nov 2011 05:00:00 +0100 5460362 http://www.medworm.com/index.php?rid=5445496&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%3D22110161%26dopt%3DAbstract Authors: Wu K, Mercier F, David OJ, Schmouder RL, Looby M Abstract Fingolimod (FTY720) is a sphingosine 1-phosphate receptor (S1PR) modulator currently being evaluated for the treatment of multiple sclerosis. Fingolimod undergoes phosphorylation in vivo to yield fingolimod phosphate (fingolimod-P), which modulates S1PRs expressed on lymphocytes and cells in the central nervous system. The authors developed a population model, using pooled data from 7 phase 1 studies, to enable characterization of fingolimod-P pharmacokinetics following oral administration of fingolimod and to evaluate the impact of key demographic variables on exposure. The fingolimod-P concentration-time course after either single or multiple doses of fingolimod was described by a 2-compartment model with first-or... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5445496 Tue, 22 Nov 2011 05:00:00 +0100 5445496 http://www.medworm.com/index.php?rid=5445494&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%3D22110162%26dopt%3DAbstract Authors: Kim H, Long-Boyle J, Rydholm N, Orchard PJ, Tolar J, Smith AR, Jacobson P, Brundage R Abstract Mycophenolate mofetil (MMF) is an immunosuppressant routinely used in allogeneic hematopoietic cell transplantation (alloHCT) to promote stem cell engraftment and prevent acute graft vs host disease. Administered as a prodrug, MMF is converted by esterases to the active moiety, mycophenolic acid (MPA). The impact of clinical covariates on unbound MPA exposure was investigated with a population pharmacokinetic approach. Pharmacokinetic data were obtained from routine area under the curve (AUC) monitoring of unbound MPA drug levels in 36 pediatric (n = 31) and young adult (n = 5) patients undergoing alloHCT for a variety of malignant and nonmalignant disorders. Unbound MPA pharmaco... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5445494 Tue, 22 Nov 2011 05:00:00 +0100 5445494 http://www.medworm.com/index.php?rid=5445493&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%3D22110163%26dopt%3DAbstract Authors: Bain G, King CD, Brittain J, Hartung JP, Dearmond I, Stearns B, Truong YP, Hutchinson JH, Evans JF, Holme K Abstract The prostaglandin D(2) receptor type 2 (DP2) and its ligand, PGD(2), have been implicated in the development of asthma and other inflammatory diseases. The authors evaluated the pharmacodynamics, pharmacokinetics and safety of [2'-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4'-trifluoromethyl-biphenyl-3-yl]-acetic acid sodium salt (AM211), a novel and potent DP2 antagonist, in healthy participants. Single and multiple doses of AM211 demonstrated dose-dependent inhibition of eosinophil shape change in blood with near-complete inhibition observed at trough after dosing 200 mg once daily for 7 days. Maximum plasma concentrations and exposures of AM211 increased i... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5445493 Tue, 22 Nov 2011 05:00:00 +0100 5445493 http://www.medworm.com/index.php?rid=5445489&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%3D22110164%26dopt%3DAbstract Conclusion: Both timolol formulations show similar and significant circadian efficacy and have minimal effects on BP and calculated diastolic ocular perfusion pressure. PMID: 22110164 [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=5445489 Tue, 22 Nov 2011 05:00:00 +0100 5445489 http://www.medworm.com/index.php?rid=5445497&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%3D22105431%26dopt%3DAbstract In conclusion, Koreans display higher NAT2 activity than Swedes regardless of NAT2 genotype. Ethnicity, OC use, and genotype determine NAT2 activity, whereas sex is the only determinant of XO activity. PMID: 22105431 [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=5445497 Mon, 21 Nov 2011 05:00:00 +0100 5445497 http://www.medworm.com/index.php?rid=5426874&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%3D22090363%26dopt%3DAbstract Authors: Lomas DA, Lipson DA, Miller BE, Willits L, Keene O, Barnacle H, Barnes NC, Tal-Singer R Abstract The aims were to determine the effect of an oral inhibitor of the signaling mediator p38 mitogen-activated protein kinase (GW856553, losmapimod) on sputum neutrophils, pulmonary function, and blood biomarkers of inflammation in chronic obstructive pulmonary disease (COPD). Three hundred and two individuals with GOLD stage II COPD were randomized to oral losmapimod 7.5 mg twice daily, inhaled salmeterol/fluticasone propionate 50 μg/500 μg combination (SFC), or placebo in a 12-week, randomized, double-blind, double-dummy study (MKI102428/NCT00642148). Neither losmapimod nor SFC had an effect on the primary end point of sputum neutrophils. Losmapimod was well tolerated and reduc... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5426874 Wed, 16 Nov 2011 05:00:00 +0100 5426874 http://www.medworm.com/index.php?rid=5426875&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%3D22075232%26dopt%3DAbstract The objective of this study was to determine whether escitalopram is associated with an increased risk for major malformations or other adverse outcomes following use in pregnancy. The authors analyzed pregnancy outcomes in women exposed to escitalopram (n = 212) versus other antidepressants (n = 212) versus nonteratogenic exposures (n = 212) and compared the outcomes. Among the escitalopram exposures were 172 (81%) live births, 32 (15%) spontaneous abortions, 6 (2.8%) therapeutic abortions, 3 stillbirths (1.7%), and 3 major malformations (1.7%). The only significant differences among groups was the rate of low birth weight (<2500 g) and overall mean birth weight (P = .225). However, spontaneous abortion rates were higher in both antidepressant groups (15% and 16%) compared with control... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5426875 Fri, 11 Nov 2011 05:00:00 +0100 5426875 http://www.medworm.com/index.php?rid=5426877&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%3D22067196%26dopt%3DAbstract Authors: Välitalo P, Kumpulainen E, Manner M, Kokki M, Lehtonen M, Hooker AC, Ranta VP, Kokki H Abstract The aim of this study was to characterize pediatric pharmacokinetics and central nervous system exposure of naproxen after oral administration. The pharmacokinetics of naproxen was studied in 53 healthy children aged 3 months to 12 years undergoing surgery with spinal anesthesia. Children received preoperatively a single dose of 10 mg/kg oral naproxen suspension. A single cerebrospinal fluid (CSF) sample (n = 52) was collected at the induction of anesthesia, and plasma samples (n = 270) were collected before, during, and after the operation (up to 51 hours after administration). A population pharmacokinetic model was built using the NONMEM software. Naproxen concentrations in p... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5426877 Tue, 08 Nov 2011 05:00:00 +0100 5426877 http://www.medworm.com/index.php?rid=5426876&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%3D22067197%26dopt%3DAbstract Authors: Taubel J, Wong AH, Naseem A, Ferber G, Camm AJ Abstract The effect of food was investigated under conditions of a thorough QT (TQT) study and with confirmation of assay sensitivity by the use of a positive control (400 mg of moxifloxacin). Fifty-five healthy subjects were randomized to treatment and a sequence of fasted and fed baseline electrocardiography days. Subjects received standard breakfast 30 to 10 minutes prior to dosing. Measurement of QT interval was performed automatically with subsequent manual onscreen overreading using electronic calipers. A profound increase in heart rate of 9.4 bpm was observed in the fed condition compared with the fasted condition at 1.5 hours after dose with a corresponding shortening of QT (27 milliseconds); (baseline data). When corr... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5426876 Tue, 08 Nov 2011 05:00:00 +0100 5426876 http://www.medworm.com/index.php?rid=5426878&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%3D22058388%26dopt%3DAbstract Authors: Naseem A, Harada T, Wang D, Arezina R, Lorch U, Onel E, Camm AJ, Taubel J PMID: 22058388 [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=5426878 Fri, 04 Nov 2011 04:00:00 +0100 5426878 http://www.medworm.com/index.php?rid=5382792&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%3D22045829%26dopt%3DAbstract Authors: Hamrén B, Ohman KP, Svensson MK, Karlsson MO Abstract The effects of tesaglitazar on renal function (assessed as urinary clearance of (125)I-sodium iothalamate or estimated by the modification of diet in renal disease formula) were studied in a 24-week open-label trial in type 2 diabetes mellitus patients randomized to daily doses of either tesaglitazar 2 mg or pioglitazone 45 mg. The aim of the analysis was to develop a population pharmacokinetic-pharmacodynamic model that could simultaneously describe the interrelationship between tesaglitazar exposure and reduction in renal function over time in patients with type 2 diabetes mellitus. The pharmacokinetic-pharmacodynamic model could adequately describe the interplay between tesaglitazar and glomerular filtration rate. A... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382792 Tue, 01 Nov 2011 04:00:00 +0100 5382792 http://www.medworm.com/index.php?rid=5382791&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%3D22045830%26dopt%3DAbstract Authors: Tisdale JE, Overholser BR, Wroblewski HA, Sowinski KM, Amankwa K, Borzak S, Kingery JR, Coram R, Zipes DP, Flockhart D, Kovacs RJ Abstract Patients with heart failure (HF) are at increased risk for drug-induced torsades de pointes (TdP) due to unknown mechanisms. Our objective was to determine if sensitivity to drug-induced QT interval lengthening is enhanced in patients with HF. In this multicenter, prospective study, 15 patients with atrial fibrillation or flutter requiring conversion to sinus rhythm were enrolled: 6 patients with New York Heart Association class II to III HF (mean ejection fraction [EF], 30% ± 9%), and 9 controls (mean EF, 53% ± 6%). Patients received ibutilide 1 mg intravenously. Blood samples and 12-lead electrocardiograms were obtained prior to and... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382791 Tue, 01 Nov 2011 04:00:00 +0100 5382791 http://www.medworm.com/index.php?rid=5382790&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%3D22045831%26dopt%3DAbstract This study was a prospective, randomized, double-blinded, placebo-controlled study that included patients with hypotension. Patients were randomized to receive either N-acetylcysteine (NAC; 50 mg/kg by 4 hours followed by 100 mg/kg/d for 48 hours diluted in 5% glucose) and deferoxamine (DFX; at a single dose of 1000 mg diluted in 5% glucose) or placebo. The primary study outcome was the serum levels of markers of oxidative damage and inflammatory response. Secondary outcomes included the incidence of acute renal failure, serum creatinine at hospital discharge, intensive care unit length of stay, and length of hospital stay. Thirty patients were enrolled in the study. The use of NAC plus DFX decreased the oxidative damage parameters but not plasma interleukin-6 levels. In contrast, plasma n... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382790 Tue, 01 Nov 2011 04:00:00 +0100 5382790 http://www.medworm.com/index.php?rid=5316303&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%3D21998350%26dopt%3DAbstract Authors: Lehmann DF, Sitar DS PMID: 21998350 [PubMed - in process] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5316303 Sat, 15 Oct 2011 11:15:55 +0100 5316303 http://www.medworm.com/index.php?rid=5283296&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%3D21960668%26dopt%3DAbstract Authors: Butler K, Teng R Abstract Ticagrelor, a P2Y12 receptor antagonist, is approved in the European Union and the US for the prevention of thrombotic events in patients with acute coronary syndromes. Renal dysfunction potentially affects drug disposition. Ticagrelor pharmacokinetics, pharmacodynamics, and safety in renal impairment were assessed. A single 180-mg ticagrelor dose was administered to volunteers with severe renal impairment (creatinine clearance [CrCL] < 30 mL/min) and normal renal function (CrCL ≥ 80 mL/min; n = 10/group). Severe renal impairment did not significantly affect ticagrelor's pharmacokinetics, pharmacodynamics, or safety. Ticagrelor absorption and AR-C124910XX (active metabolite) formation were rapid. In renally impaired volunteers, ticagrelor mea... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5283296 Thu, 29 Sep 2011 04:00:00 +0100 5283296 http://www.medworm.com/index.php?rid=5283295&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%3D21960669%26dopt%3DAbstract Authors: Atiee G, Lasseter K, Baughman S, McCullough A, Collis P, Hollister A, Hernandez J Abstract Peramivir, an intravenously administered neuraminidase inhibitor, may be used concomitantly with other influenza antivirals. Two studies were conducted to assess the potential for pharmacokinetic interactions of peramivir when coadministered with oseltamivir or rimantadine. Twenty-one healthy subjects were enrolled in each randomized, open-label, crossover study, and they received 1 intravenous dose of peramivir (600 mg), 1 oral dose of oseltamivir (75 mg) or rimantadine (100 mg), or a combination of peramivir with oseltamivir or rimantadine. Assessment of the 90% confidence interval for the geometric mean ratio of peramivir and oseltamivir carboxylate or rimantadine pharmacokinetic ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5283295 Thu, 29 Sep 2011 04:00:00 +0100 5283295 http://www.medworm.com/index.php?rid=5283294&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%3D21960670%26dopt%3DAbstract Authors: Carcelero E, Soy D, Guerrero L, Poch E, Fernandez J, Castro P, Ribas J PMID: 21960670 [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=5283294 Thu, 29 Sep 2011 04:00:00 +0100 5283294 http://www.medworm.com/index.php?rid=5283301&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%3D21956604%26dopt%3DAbstract Authors: Lehr T, Haertter S, Liesenfeld KH, Staab A, Clemens A, Reilly PA, Friedman J Abstract Dabigatran, administered orally as the prodrug dabigatran etexilate (DE), is a direct thrombin inhibitor shown to be effective in the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). The aim of this analysis was to derive a modeling and simulation-based dose and dosing regimen for AF patients with severe renal failure who could potentially benefit from the use of DE. The exposure was simulated for AF patients with severe renal impairment for several combinations of doses (75, 110, 150 mg) and posologies (BID, QD, Q2D). Simulations were based on a population pharmacokinetic model derived from data from 9522 patients from the pivotal phase III study (RE-... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5283301 Wed, 28 Sep 2011 04:00:00 +0100 5283301 http://www.medworm.com/index.php?rid=5283300&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%3D21956605%26dopt%3DAbstract The objective of this work was to derive a dosing regimen for dabigatran in patients with severe renal impairment by modeling and simulation. Data from a dedicated renal impairment study were used to model the pharmacokinetics of dabigatran in normal and renal-impaired subjects. Model parameters were used to simulate the average concentration time-course of dabigatran following various dosing regimens. Pharmacokinetics of dabigatran in normal and renal-impaired subjects were best described by a 2-compartment open model with first-order absorption and elimination. Simulations were performed to select an appropriate regimen that reasonably matched the exposures on an average with those observed in subjects with moderate renal impairment who did not require a dose adjustment because of a favo... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5283300 Wed, 28 Sep 2011 04:00:00 +0100 5283300 http://www.medworm.com/index.php?rid=5283299&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%3D21956606%26dopt%3DAbstract Authors: Ben Fredj N, Aouam K, Chaabane A, Njim L, Boughattas N PMID: 21956606 [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=5283299 Wed, 28 Sep 2011 04:00:00 +0100 5283299 http://www.medworm.com/index.php?rid=5283298&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%3D21956607%26dopt%3DAbstract In conclusion, sildenafil therapy was found to be associated with improved survival in patients with idiopathic pulmonary arterial hypertension. PMID: 21956607 [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=5283298 Wed, 28 Sep 2011 04:00:00 +0100 5283298 http://www.medworm.com/index.php?rid=5283297&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%3D21956608%26dopt%3DAbstract Authors: Kreuzer P, Landgrebe M, Wittmann M, Schecklmann M, Poeppl TB, Hajak G, Langguth B Abstract Hypothermia as an adverse reaction of antipsychotic drug use represents a potentially life-threatening complication. However, the mechanisms by which antipsychotic drugs alter thermoregulatory processes in the human body are far from being fully understood. Here we present a case series of 5 patients developing severe hypothermia after administration of olanzapine and benperidol. Controlled by a network of neural structures, body temperature is physiologically regulated in far more narrow boundaries than are other vital functions, and its homeostasis is critical for survival. The preoptic region in the ventral hypothalamus is assumed to act as a coordinating center that is endowed wi... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5283297 Wed, 28 Sep 2011 04:00:00 +0100 5283297 http://www.medworm.com/index.php?rid=5283305&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%3D21953571%26dopt%3DAbstract Authors: Gupta M, Lorusso PM, Wang B, Yi JH, Burris HA, Beeram M, Modi S, Chu YW, Agresta S, Klencke B, Joshi A, Girish S Abstract Trastuzumab emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate in development for treatment of HER2-positive cancers. T-DM1 has been tested as a single agent in a phase I and 2 phase II studies of patients with heavily pretreated metastatic breast cancer (MBC), with the maximum tolerated dose established at 3.6 mg/kg intravenously for every-3-week dosing. The authors present results from the population pharmacokinetics analysis for T-DM1. Population pharmacokinetics for T-DM1 were characterized using a clinical database of 273 patients from the 3 studies. Pharmacokinetics was best described by a linear 2-compartment model. Population estimates... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5283305 Tue, 27 Sep 2011 04:00:00 +0100 5283305 http://www.medworm.com/index.php?rid=5283304&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%3D21953572%26dopt%3DAbstract Authors: Korth-Bradley JM, Troy SM, Matschke K, Muralidharan G, Fruncillo RJ, Speth JL, Raible DG Abstract The pharmacokinetic parameters of tigecycline were assessed in subjects with severe renal impairment (creatinine clearance <30 mL/min, n = 6), subjects receiving hemodialysis (4 received tigecycline before and 4 received tigecycline after hemodialysis), and subjects with age-adjusted, normal renal function (n = 6) after administration of single 100-mg doses. Serial serum and urine samples were collected and assayed using validated liquid chromatography with tandem mass spectrometer (LC/MS/MS) methods. Concentration-time data were then analyzed using noncompartmental pharmacokinetic methods. Tigecycline renal clearance in subjects with normal renal function represented appro... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5283304 Tue, 27 Sep 2011 04:00:00 +0100 5283304 http://www.medworm.com/index.php?rid=5283303&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%3D21953573%26dopt%3DAbstract This study shows, for the first time, that vardenafil has a favorable acute effect on aortic stiffness and wave reflection in ED patients. PMID: 21953573 [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=5283303 Tue, 27 Sep 2011 04:00:00 +0100 5283303 http://www.medworm.com/index.php?rid=5283302&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%3D21953574%26dopt%3DAbstract Authors: Ben Fredj N, Aouam K, Chaabane A, Braham D, Boughattas NA PMID: 21953574 [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=5283302 Tue, 27 Sep 2011 04:00:00 +0100 5283302 http://www.medworm.com/index.php?rid=5283307&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%3D21947370%26dopt%3DAbstract The objective of this investigation was to develop a mechanistic population model to characterize the pharmacokinetics of mavrilimumab, the GM-CSFRα-mediated clearance, and receptor occupancy following single intravenous dosing to patients with rheumatoid arthritis. The internalization rate of mavrilimumab-GM-CSFRα complex was fixed to a value determined from quantitative confocal fluorescent imaging. The estimated typical first-order clearance and the central and peripheral distribution volumes were 3.79 mL/kg/d, 39.6 mL/kg, and 50.3 mL/kg, respectively. The systemic GM-CSFRα expression level was estimated to be 0.0782 nM, and the equilibrium dissociation constant (0.103 nM) was in good agreement with the monovalent affinity determined by surface plasmon resonance. By fitting to the ob... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5283307 Fri, 23 Sep 2011 04:00:00 +0100 5283307 http://www.medworm.com/index.php?rid=5283306&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%3D21947371%26dopt%3DAbstract Authors: Basile AS, Hutmacher M, Nickens D, Nielsen J, Kowalski K, Whitfield L, Masayo O, Nakane M Abstract The anti-vascular endothelial growth factor (VEGF) aptamer pegaptanib is eliminated primarily by renal clearance. Because renal function declines with age, pegaptanib exposure in patients with age-related macular degeneration (AMD) may increase. Therefore, a population pharmacokinetic (PK) analysis of pegaptanib was undertaken in Western and Asian AMD patients to determine the influence of renal function on apparent pegaptanib clearance (CL). Pegaptanib (0.3-3 mg per eye) was administered every 4 to 6 weeks to 262 AMD patients in 4 studies. Pegaptanib exposures (area under the concentration-time curve [AUC] and maximum plasma concentration) after 8 doses were similar to expos... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5283306 Fri, 23 Sep 2011 04:00:00 +0100 5283306 http://www.medworm.com/index.php?rid=5249599&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%3D21940716%26dopt%3DAbstract Authors: Noertersheuser PA, Pradhan RS, Klein CE, Williams LA, Palaparthy R, Garimella TS, Lichtenberger O, Awni WM Abstract Paricalcitol injection and capsules are approved for the prevention and treatment of secondary hyperparathyroidism. Exposure-response analyses were performed to describe paricalcitol pharmacokinetics and the relationship to clinical responses (intact parathyroid hormone [iPTH], serum calcium, and phosphorus) following administration of paricalcitol capsules or injection to patients with chronic kidney disease (stage 5). Paricalcitol pharmacokinetics were similar following intravenous and oral administration with mean oral clearance of 1.75 L/h and bioavailability of 75.1%. Exposure-clinical response was best described by an indirect effects model where serum ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5249599 Thu, 22 Sep 2011 04:00:00 +0100 5249599 http://www.medworm.com/index.php?rid=5221249&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%3D21908878%26dopt%3DAbstract Authors: Comets E, Brendel K, Mentré F PMID: 21908878 [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=5221249 Sat, 10 Sep 2011 04:00:00 +0100 5221249 http://www.medworm.com/index.php?rid=5221248&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%3D21908879%26dopt%3DAbstract Authors: Brass EP, Hiatt WR PMID: 21908879 [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=5221248 Sat, 10 Sep 2011 04:00:00 +0100 5221248 http://www.medworm.com/index.php?rid=5221253&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%3D21903891%26dopt%3DAbstract Authors: Kees MG, Steinke T, Moritz S, Rupprecht K, Paulus EM, Kees F, Bucher M, Faerber L Abstract In 2 crossover studies, 12 healthy volunteers (6 male/6 female) received a single oral dose of mycophenolate mofetil (MMF) 1000 mg or an equimolar dose of enteric-coated mycophenolate sodium (EC-MPS) 720 mg fasting with and without coadministered omeprazole 20 mg bid. The plasma concentrations of mycophenolic acid (MPA) and of the inactive metabolite mycophenolic acid glucuronide (MPA-G) were measured by high-performance liquid chromatography (HPLC). In addition, dissolution of MMF 500 mg or EC-MPS 360 mg tablets was determined using an USP paddle apparatus in aqueous buffer of pH 1 to 7. The bioavailability of MPA following administration of MMF or EC-MPS was similar except for the ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5221253 Thu, 08 Sep 2011 04:00:00 +0100 5221253 http://www.medworm.com/index.php?rid=5221252&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%3D21903892%26dopt%3DAbstract Authors: Saddichha S, Kumar R, Babu GN, Chandra P PMID: 21903892 [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=5221252 Thu, 08 Sep 2011 04:00:00 +0100 5221252 http://www.medworm.com/index.php?rid=5221251&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%3D21903893%26dopt%3DAbstract Authors: Darwish M, Bond M, Hellriegel ET, Youakim JM, Yang R, Robertson P Abstract The wakefulness-promoting medication armodafinil (R-modafinil) is being studied as an adjunctive treatment for patients with schizophrenia receiving antipsychotic therapy. This open-label study in 37 adults with schizophrenia evaluated whether a drug-drug interaction occurs between armodafinil (a moderate CYP3A4 inducer) and the atypical antipsychotic quetiapine (primarily metabolized by CYP3A4). Patients were required to be on a stable dose of quetiapine ≥300 mg once daily in the evening before enrollment. Steady-state quetiapine pharmacokinetics were determined following daily administration of quetiapine alone in the evening (day 5) and then following concomitant armodafinil administration (tit... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5221251 Thu, 08 Sep 2011 04:00:00 +0100 5221251 http://www.medworm.com/index.php?rid=5221250&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%3D21903894%26dopt%3DAbstract Authors: Wang Z, Lee B, Pearce D, Qian S, Wang Y, Zhang Q, Chow MS Abstract Meclizine, an antihistamine, has been widely used for prophylactic treatment and management of motion sickness. However, the onset of action of meclizine was about 1 hour for the treatment of motion sickness and vertigo. A new suspension formulation of meclizine (MOS) was developed with the intention to achieve a rapid effect. To investigate the pharmacokinetics of the new MOS formulation versus the marketed meclizine oral tablet (MOT), a phase 1 pharmacokinetic study was performed in 20 healthy volunteers. In addition, an in vitro metabolic study using human hepatic microsome and recombinant CYP enzyme was also performed to determine the metabolic pathway in the human body. The plasma concentration of MOS ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5221250 Thu, 08 Sep 2011 04:00:00 +0100 5221250 http://www.medworm.com/index.php?rid=5195406&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%3D21885687%26dopt%3DAbstract In this study, the authors developed a phenotyping method for CYP1A2, 2C9, 2C19, 2D6, and 3A4 using a cocktail of 100 mg caffeine, 125 mg tolbutamide, 20 mg omeprazole, 30 mg dextromethorphan, and 2 mg midazolam. A simple sampling scheme was established collecting 3 blood samples at 0, 4, and 24 hours followed by solid-phase extraction and liquid chromatography/tandem mass spectrometry analysis. After addition of 8 deuterated internal standards and extraction, the analytes were separated using gradient elution with ammonium acetate and methanol. Data acquisition was performed on a triple quadrupole linear ion trap mass spectrometer in multiple-reaction monitoring mode with positive electrospray ionization. The assay was validated according to international guidelines: limits of quantificat... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5195406 Wed, 31 Aug 2011 23:00:00 +0100 5195406 http://www.medworm.com/index.php?rid=5142560&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%3D21835975%26dopt%3DAbstract Authors: PMID: 21835975 [PubMed - in process] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5142560 Sat, 20 Aug 2011 09:18:06 +0100 5142560 http://www.medworm.com/index.php?rid=5012174&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%3D21724950%26dopt%3DAbstract Authors: Willis BA, Zhang W, Ayan-Oshodi M, Lowe SL, Annes WF, Sirois PJ, Friedrich S, de la Peña A Semagacestat, a γ-secretase inhibitor, reduces formation of amyloid beta peptide. Two single-dose (140 mg), open-label, randomized, 3-period, crossover studies evaluated the effect of formulation, food, and time of dosing on the pharmacokinetics and pharmacodynamics of semagacestat in healthy participants. The first study (n = 14) compared tablet to capsules. For all formulations, the median time to maximum plasma concentration (t(max)) was generally 1.0 hour. Plasma elimination was rapid, with a half-life of approximately 2.5 hours. Tablet form II bioavailability (F) relative to capsule was approximately 100% (F = 1.03 [90% confidence interval (CI), 0.96-1.10]). In the second study, p... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=5012174 Thu, 30 Jun 2011 23:00:00 +0100 5012174 http://www.medworm.com/index.php?rid=4969149&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%3D21666147%26dopt%3DAbstract Response to "role of orally available antagonists of factor xa in the treatment and prevention of thromboembolic disease: focus on rivaroxaban". J Clin Pharmacol. 2011 Jul;51(7):1122-3 Authors: Turpie AG PMID: 21666147 [PubMed - in process] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4969149 Mon, 27 Jun 2011 06:15:35 +0100 4969149 http://www.medworm.com/index.php?rid=4969147&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%3D21680781%26dopt%3DAbstract In conclusion, quercetin significantly induced CYP3A activity to substrate midazolam, and the induction was partly related to the CYP3A5 genotype, being more prominent in CYP3A5*1/*1 and CYP3A5*1/*3 individuals. PMID: 21680781 [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=4969147 Wed, 15 Jun 2011 23:00:00 +0100 4969147 http://www.medworm.com/index.php?rid=4969146&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%3D21680782%26dopt%3DAbstract This study clinically evaluated a novel PEGylated form of interferon beta-1a (PEG-IFN beta-1a), a potential first-line treatment for relapsing multiple sclerosis, in healthy volunteers. Two randomized, blinded phase I studies were conducted: a single-dose study (n = 60) comparing subcutaneous or intramuscular PEG-IFN beta-1a (63, 125, or 188 μg) with intramuscular unmodified IFN beta-1a 30 μg and a multiple-dose study (n = 69) comparing subcutaneous PEG-IFN beta-1a dosed once every 2 or 4 weeks with placebo. Assessments included pharmacokinetic and pharmacodynamic (serum neopterin and 2',5'-OAS) measures, exploratory immune assessments, safety, and tolerability. A dose-proportional increase in PEG-IFN beta-1a exposure was observed, with a 4-fold greater exposure at 63 μg (6 million inte... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4969146 Wed, 15 Jun 2011 23:00:00 +0100 4969146 http://www.medworm.com/index.php?rid=4969148&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%3D21673137%26dopt%3DAbstract This study assessed the safety, tolerability, and pharmacokinetics (PK) of a continuous infusion of pasireotide in healthy volunteers. In this single-center, open-label, dose escalation study, healthy male volunteers received a 7-day continuous SC infusion of pasireotide in sequential ascending-dose cohorts. Single and/or 8-hour blood samples were taken on days 1 to 10 to assess PK and on days 1, 2, and 7 and a control day to assess glucose metabolism. Adverse events were evaluated throughout. Forty-four participants were enrolled into 8 cohorts: pasireotide 450, 900, 1350, 1800 (3 cohorts were enrolled at this dose level), 2250, and 2025 μg/d. Doses were well tolerated up to 2025 μg/d. Adverse events were generally mild and gastrointestinal. Pasireotide steady-state clearance was reduce... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4969148 Mon, 13 Jun 2011 23:00:00 +0100 4969148 http://www.medworm.com/index.php?rid=4922369&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%3D21659624%26dopt%3DAbstract Authors: Mao ZL, Townsend RW, Gao C, Wheeler JJ, Kastrissios H, Keirns J Vernakalant hydrochloride is a novel, predominantly atrial-selective antiarrhythmic drug that effectively and rapidly terminates atrial fibrillation (AF). Plasma vernakalant concentration data from 5 phase 2 and 3 clinical trials of vernakalant in patients with AF or atrial flutter and a phase 1 study in healthy volunteers were used to construct a population pharmacokinetic model. Plasma vernakalant concentration-time data were best fit by a 2-compartment mammillary model, with rapid first-order elimination from the central compartment. Median systemic clearance was 0.35 L/h/kg (or 28 L/h for an 80-kg patient), with intersubject variability estimated to be 40%. Clearance was significantly influenced by CYP2D6 geno... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4922369 Wed, 08 Jun 2011 23:00:00 +0100 4922369 http://www.medworm.com/index.php?rid=4922368&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%3D21659625%26dopt%3DAbstract In conclusion, this model describes disease progression in Alzheimer patients using novel covariates that are important for understanding the worsening of ADAS-cog scores over time and may be useful in the future for optimizing study designs through clinical trial simulations. PMID: 21659625 [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=4922368 Wed, 08 Jun 2011 23:00:00 +0100 4922368 http://www.medworm.com/index.php?rid=4922367&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%3D21659626%26dopt%3DAbstract In conclusion, aliskiren/HCT SPCs are pharmacokinetically and pharmacodynamically bioequivalent to aliskiren and HCT in free combination. PMID: 21659626 [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=4922367 Wed, 08 Jun 2011 23:00:00 +0100 4922367 http://www.medworm.com/index.php?rid=4922366&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%3D21659627%26dopt%3DAbstract Authors: Syed S, Clemens PL, Lathers D, Kollia G, Dhar A, Walters I, Masson E Brivanib alaninate is the orally available prodrug of brivanib, a dual inhibitor of fibroblast growth factor and vascular endothelial growth factor signaling pathways that is under therapeutic investigation for various malignancies. Brivanib alaninate inhibits CYP3A4 in vitro, and thus there is potential for drug-drug interaction with CYP3A4 substrates, such as midazolam. The present study evaluated pharmacokinetic parameters and safety/tolerability upon coadministration of brivanib alaninate and midazolam. Healthy participants received intravenous (IV) or oral midazolam with and without oral brivanib alaninate. Blood samples for pharmacokinetic analysis were collected up to 12 hours after midazolam and up to... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4922366 Wed, 08 Jun 2011 23:00:00 +0100 4922366 http://www.medworm.com/index.php?rid=4922365&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%3D21659628%26dopt%3DAbstract Authors: Holzgrefe HH, Ferber G, Morrison R, Meyer O, Greiter-Wilke A, Singer T The authors have previously demonstrated rate-independent QT variability in the dog and cynomolgus monkey, where the QT associated with any RR was a normally distributed value that was accurately evaluated as the distribution mean. The present study investigated the rate-independent characteristics of the human QT. Digital electrocardiographs (1000 Hz) were collected for 24 hours in 51 patients (thorough QT study) and analyzed by computer. Distribution-based analysis was applied to the placebo and moxifloxacin (400 mg) arms to characterize the nature of the QT interval and to assess the efficacy of distribution-based analysis for QTc determination. Novel statistics using continuous means and bootstrapped 95... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4922365 Wed, 08 Jun 2011 23:00:00 +0100 4922365 http://www.medworm.com/index.php?rid=4922364&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%3D21659629%26dopt%3DAbstract Authors: Tong SE, Daniels SE, Black P, Chang S, Protter A, Desjardins PJ SCIO-469 is a selective p38α mitogen-activated protein kinase (MAPK) inhibitor for preclinical models of acute pain. This prospective, double-blind, randomized clinical study compared efficacy and safety of oral SCIO-469, ibuprofen, and placebo in postsurgical dental pain. Subjects (n = 263) undergoing extraction of 1 or more impacted mandibular third molars received preoperative treatment with SCIO-469 (150, 210, or 300 mg), ibuprofen (400 mg), or placebo; the 210-mg group received 90 mg postoperatively. A 4-point categorical scale and a 100-mm visual analogue scale were used to measure pain intensity. The primary end point was median time from first incision to first rescue medication using the Kaplan-Meier pro... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4922364 Wed, 08 Jun 2011 23:00:00 +0100 4922364 http://www.medworm.com/index.php?rid=4922372&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%3D21646440%26dopt%3DAbstract Authors: Malati CY, Robertson SM, Hunt JD, Chairez C, Alfaro RM, Kovacs JA, Penzak SR A number of herbal preparations have been shown to interact with prescription medications secondary to modulation of cytochrome P450 (CYP) and/or P-glycoprotein (P-gp). The purpose of this study was to determine the influence of Panax ginseng on CYP3A and P-gp function using the probe substrates midazolam and fexofenadine, respectively. Twelve healthy participants (8 men) completed this open-label, single-sequence pharmacokinetic study. Healthy volunteers received single oral doses of midazolam 8 mg and fexofenadine 120 mg, before and after 28 days of P ginseng 500 mg twice daily. Midazolam and fexofenadine pharmacokinetic parameter values were calculated and compared before and after P ginseng admini... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4922372 Sun, 05 Jun 2011 23:00:00 +0100 4922372 http://www.medworm.com/index.php?rid=4922371&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%3D21646441%26dopt%3DAbstract Authors: Ahn JE, Plan EL, Karlsson MO, Miller R The purpose of this study was to describe longitudinal daily seizure count data with respect to the effects of time and pregabalin add-on therapy. Models were developed in a stepwise manner: base model, time effect model, and time and drug effect (final) model, using a negative binomial distribution with Markovian features. Mean daily seizure count (λ) was estimated to be 0.385 (relative standard error [RSE] 3.09%) and was further increased depending on the seizure count on the previous day. An overdispersion parameter (OVDP), representing extra-Poisson variation, was estimated to be 0.330 (RSE 11.7%). Interindividual variances on λ and OVDP were 84.7% and 210%, respectively. Over time, λ tended to increase exponentially with a rate co... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4922371 Sun, 05 Jun 2011 23:00:00 +0100 4922371 http://www.medworm.com/index.php?rid=4922370&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%3D21646442%26dopt%3DAbstract Authors: Saunders DL, Messina J, Darwish M, Xie F, Leary KJ, Cantilena LR This exploratory randomized, double-blind, placebo-controlled, 5-treatment, 5-period crossover study was conducted using a thermally induced hyperalgesia pain model in 51 healthy volunteers (33 evaluable) to characterize the relative potency of fentanyl buccal tablet (FBT) versus intravenous morphine. Relative potency was assessed using the sum of pain intensity differences over 60 minutes after the application of a 43°C, 46°C, and 49°C painful stimulus following thermally induced hyperalgesia. Relative potency was also assessed by pupil diameter and responses to subjective questionnaires. The relative potency of FBT was 46.2 times that of intravenous morphine (95% confidence interval [CI], 17.6-575.3) based o... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4922370 Sun, 05 Jun 2011 23:00:00 +0100 4922370 http://www.medworm.com/index.php?rid=4922374&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%3D21642470%26dopt%3DAbstract Authors: Tyl B, Kabbaj M, Azzam S, Sologuren A, Valiente R, Reinbolt E, Roupe K, Blanco N, Wheeler W The effect of bilastine on cardiac repolarization was studied in 30 healthy participants during a multiple-dose, triple-dummy, crossover, thorough QT study that included 5 arms: placebo, active control (400 mg moxifloxacin), bilastine at therapeutic and supratherapeutic doses (20 mg and 100 mg once daily, respectively), and bilastine 20 mg administered with ketoconazole 400 mg. Time-matched, triplicate electrocardiograms (ECGs) were recorded with 13 time points extracted predose and 16 extracted over 72 hours post day 4 dosing. Four QT/RR corrections were implemented: QTcB; QTcF; a linear individual correction (QTcNi), the primary correction; and a nonlinear one (QTcNnl). Moxifloxacin w... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4922374 Thu, 02 Jun 2011 23:00:00 +0100 4922374 http://www.medworm.com/index.php?rid=4922373&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%3D21642471%26dopt%3DAbstract Authors: Shroads AL, Langaee T, Coats BS, Kurtz TL, Bullock JR, Weithorn D, Gong Y, Wagner DA, Ostrov DA, Johnson JA, Stacpoole PW Dichloroacetate (DCA), a chemical relevant to environmental science and allopathic medicine, is dehalogenated by the bifunctional enzyme glutathione transferase zeta (GSTz1)/maleylacetoacetate isomerase (MAAI), the penultimate enzyme in the phenylalanine/tyrosine catabolic pathway. The authors postulated that polymorphisms in GSTz1/MAAI modify the toxicokinetics of DCA. GSTz1/MAAI haplotype significantly affected the kinetics and biotransformation of 1,2-(13)C-DCA when it was administered at either environmentally (μg/kg/d) or clinically (mg/kg/d) relevant doses. GSTz1/MAAI haplotype also influenced the urinary accumulation of potentially toxic tyrosine me... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4922373 Thu, 02 Jun 2011 23:00:00 +0100 4922373 http://www.medworm.com/index.php?rid=4922380&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%3D21628599%26dopt%3DAbstract Authors: Sterke CS, van Beeck EF, van der Velde N, Ziere G, Petrovic M, Looman CW, van der Cammen TJ The contribution of specific psychotropic drugs to fall risk in patients with dementia has not been quantified precisely until now. The authors evaluated the dose-response relationship between psychotropic drugs and falls in nursing home residents with dementia. Daily drug use and daily falls were recorded in 248 nursing home residents with dementia from January 1, 2006, to January 1, 2008. For each day of thez study period, data on drug use were abstracted from the prescription database, and falls were retrieved from a standardized incident report system, resulting in a data set of 85 074 person-days. The authors found significant dose-response relationships for the use of anti-psychot... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4922380 Mon, 30 May 2011 23:00:00 +0100 4922380 http://www.medworm.com/index.php?rid=4922379&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%3D21628600%26dopt%3DAbstract Authors: Chen JJ, Wilkinson JR Rasagiline is an irreversible monoamine oxidase type B (MAO-B) inhibitor indicated for the treatment of the signs and symptoms of idiopathic Parkinson disease as initial monotherapy and as adjunct therapy to levodopa. Pharmacologic inhibition of monoamine oxidase type A (MAO-A), but not MAO-B, poses a risk of the "cheese effect," a hypertensive response to excess dietary tyramine, a biogenic sympathomimetic amine. Tyramine challenge studies, conducted to characterize rasagiline selectivity for the MAO-B enzyme and tyramine sensitivity, demonstrate that rasagiline, when used at the recommended dose, is selective for MAO-B and is not associated with heightened tyramine sensitivity. This conclusion is also supported by safety results from large clinical tria... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4922379 Mon, 30 May 2011 23:00:00 +0100 4922379 http://www.medworm.com/index.php?rid=4922378&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%3D21628601%26dopt%3DAbstract Authors: Riesmeyer JS, Salazar DE, Weerakkody GJ, Ni L, Wrishko RE, Ernest CS, Luo J, Li YG, Small DS, Rohatagi S, Macias WL In TRITON-TIMI 38, levels of the prasugrel active metabolite (pras-AM) were measured in a population pharmacokinetic substudy that characterized the intrinsic and extrinsic factors influencing exposure. Higher exposure to the pras-AM was observed in low-weight or very elderly patients. The authors hypothesized that this higher exposure might explain the higher risk of non-coronary artery bypass graft (CABG)-related TIMI-related bleeding observed in these 2 patient populations. The relationship between estimated exposure to the pras-AM and clinical outcomes was assessed in 1159 prasugrel-treated patients enrolled in the substudy using multivariable logistic regres... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4922378 Mon, 30 May 2011 23:00:00 +0100 4922378 http://www.medworm.com/index.php?rid=4922377&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%3D21628602%26dopt%3DAbstract In conclusion, there are no pharmacokinetic drug interactions between naproxen and esomeprazole. The NAP/ESO tablet is bioequivalent to EC naproxen, and as expected, the bioavailability of non-EC esomeprazole from the NAP/ESO tablet is lower than the EC esomeprazole formulation. PMID: 21628602 [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=4922377 Mon, 30 May 2011 23:00:00 +0100 4922377 http://www.medworm.com/index.php?rid=4922376&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%3D21628603%26dopt%3DAbstract In conclusion, the low and short-lived bioavailability of aclidinium and the low incidence of systemic side effects contribute to its positive safety and tolerability profile. PMID: 21628603 [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=4922376 Mon, 30 May 2011 23:00:00 +0100 4922376 http://www.medworm.com/index.php?rid=4922375&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%3D21628604%26dopt%3DAbstract Authors: Gerrits MG, de Greef R, Dogterom P, Peeters PA Asenapine is indicated for treatment of schizophrenia in the United States and acute treatment of manic or mixed episodes, as monotherapy (United States and European Union) or adjunct therapy (United States only), associated with bipolar I disorder. It is extensively metabolized; the 2 main metabolites are asenapine N-glucuronide and N-desmethyl-asenapine. The authors investigated the pharmacokinetic interactions between asenapine and valproate in an open-label, randomized, 2-way crossover study. Twenty-four healthy male volunteers received sublingual doses of asenapine 5 mg alone or under steady-state valproate (500 mg bid for 9 days). Blood samples collected until 72 hours postdosing were analyzed for asenapine, N-desmethyl-asen... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4922375 Mon, 30 May 2011 23:00:00 +0100 4922375 http://www.medworm.com/index.php?rid=4876583&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%3D21617016%26dopt%3DAbstract Authors: Lee J, Hwang Y, Kang W, Seong SJ, Lim MS, Lee HW, Yim DS, Sohn DR, Han S, Yoon YR Population pharmacokinetic (PK) and pharmacodynamic (PD) modeling of clopidogrel was developed from pooled data from healthy volunteers (n = 44) and stroke patients (n = 35). The PK modeling used plasma concentrations of the clopidogrel metabolite (SR26334), and the PD modeling used platelet aggregation. The models were developed using NONMEM and evaluated via visual predictive check (VPC). Data were analyzed by 2-compartment modeling with Erlang's absorption and first-order elimination. There was no statistically significant covariate for each model parameter. The typical point estimates of PK were k(tr) (identical transfer rate constant) = 5.97 h(-1), k(e) (elimination rate constant) = 0.126 h(... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4876583 Wed, 25 May 2011 23:00:00 +0100 4876583 http://www.medworm.com/index.php?rid=4876590&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%3D21610201%26dopt%3DAbstract Authors: Naik H, Vakilynejad M, Wu J, Viswanathan P, Dote N, Higuchi T, Leifke E TAK-875 is a selective G-protein-coupled receptor 40 agonist in development for the treatment of type 2 diabetes mellitus. This randomized, double-blind, placebo-controlled study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-875 following administration of a single oral dose of TAK-875 (25-800 mg) in 60 healthy volunteers. TAK-875 was eliminated slowly with a mean terminal elimination t(frac12) of approximately 28.1 to 36.6 hours. Systemic exposure of TAK-875 did not exhibit dose-proportional increases across the dose range evaluated due to a greater than proportional increase in exposure at doses greater than 200 mg. A preliminary food effect assessment indicated that c... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4876590 Mon, 23 May 2011 23:00:00 +0100 4876590 http://www.medworm.com/index.php?rid=4876589&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%3D21610202%26dopt%3DAbstract Authors: Harder S Anticoagulants are widely used to prevent and treat venous thromboembolism, prevent stroke in atrial fibrillation, and manage acute coronary syndrome. These drugs are often used in elderly patients, who commonly have renal impairment, comorbidities, and polypharmacy. Renal impairment is a risk factor for bleeding and thrombosis during anticoagulant therapy and can influence the balance between the safety and efficacy of such agents. Some of the more established anticoagulants, such as the low-molecular-weight heparins, warfarin, and fondaparinux, are contraindicated for use in patients with severe renal impairment. Of the new oral anticoagulants, dabigatran etexilate, rivaroxaban, and apixaban are at the most advanced stages of development. Dabigatran requires dose ad... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4876589 Mon, 23 May 2011 23:00:00 +0100 4876589 http://www.medworm.com/index.php?rid=4876588&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%3D21610203%26dopt%3DAbstract Authors: Lofwall MR, Moody DE, Fang WB, Nuzzo PA, Walsh SL PMID: 21610203 [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=4876588 Mon, 23 May 2011 23:00:00 +0100 4876588 http://www.medworm.com/index.php?rid=4876587&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%3D21610204%26dopt%3DAbstract In conclusion, atorvastatin lowered both LDL-C and hs-CRP to a similar degree in patients of South Asian or European origin, suggesting usual starting doses of atorvastatin (with appropriate monitoring), rather than lower starting doses as has been advocated by some, may be used in patients of South Asian origin. PMID: 21610204 [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=4876587 Mon, 23 May 2011 23:00:00 +0100 4876587 http://www.medworm.com/index.php?rid=4876586&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%3D21610205%26dopt%3DAbstract This study demonstrates that gastric-retentive ER dosage forms may reduce dose frequency while minimizing the plasma peak-to-trough fluctuation and consequently reduce motor fluctuation in patients with Parkinson's disease. PMID: 21610205 [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=4876586 Mon, 23 May 2011 23:00:00 +0100 4876586 http://www.medworm.com/index.php?rid=4876585&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%3D21610206%26dopt%3DAbstract The objective of the study was to evaluate the effect of hepatic impairment on the pharmacokinetics of tonapofylline. Patients with mild or moderate hepatic impairment were enrolled in parallel with demographically matched healthy subjects. All study participants received a single 75-mg oral tonapofylline capsule. Thepharmacokinetic parameters for both tonapofylline and its active metabolite, acyl-glucuronide (tonapofylline-AG), were affected by hepatic impairment significantly (P <.1) except for time to peak plasma concentration (t(max)), terminal half-life (t(½)), and apparent volume of distribution based on the terminal phase (Vdz/F). In the mild group, peak plasma concentration (C(max)), area under the time-concentration curve from time 0 to 48 hours postdose (AUC(48h)), ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4876585 Mon, 23 May 2011 23:00:00 +0100 4876585 http://www.medworm.com/index.php?rid=4876584&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%3D21610207%26dopt%3DAbstract Authors: Nathan PJ, O'Neill BV, Bush MA, Koch A, Tao WX, Maltby K, Napolitano A, Brooke AC, Skeggs AL, Herman CS, Larkin AL, Ignar DM, Richards DB, Williams PM, Bullmore ET Endogenous opioids and μ-opioid receptors have been linked to hedonic and rewarding aspects of palatable food intake. The authors examined the safety, pharmacokinetic, and pharmacodynamic profile of GSK1521498, a μ-opioid receptor inverse agonist that is being investigated primarily for the treatment of overeating behavior in obesity. In healthy participants, GSK1521498 oral solution and capsule formulations were well tolerated up to a dose of 100 mg. After single doses (10-150 mg), the maximum concentration (C(max)) and area under the curve (AUC) in plasma increased in a dose-proportional manner. GSK1521498 selec... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4876584 Mon, 23 May 2011 23:00:00 +0100 4876584 http://www.medworm.com/index.php?rid=4876593&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%3D21602517%26dopt%3DAbstract Authors: Shi JG, Chen X, Emm T, Scherle PA, McGee RF, Lo Y, Landman RR, McKeever EG, Punwani NG, Williams WV, Yeleswaram S Ruxolitinib, a selective Janus kinase (JAK) 1&2 inhibitor in development for the treatment of myeloproliferative neoplasms, is primarily metabolized by CYP3A4. The effects of inhibition or induction of CYP3A4 on single oral dose ruxolitinib pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated in healthy volunteers. Coadministration of ketoconazole (a potent CYP3A4 inhibitor) and erythromycin (a moderate CYP3A4 inhibitor) increased total ruxolitinib plasma exposure (AUC(0-∞)) by 91% and 27%, respectively, and ruxolitinib PD, as measured by the inhibition of interleukin (IL)-6-stimulated STAT3 phosphorylation in whole blood, was generally consistent w... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4876593 Thu, 19 May 2011 23:00:00 +0100 4876593 http://www.medworm.com/index.php?rid=4876592&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%3D21602518%26dopt%3DAbstract Authors: Schiavon G, Eechoute K, Mathijssen RH, de Bruijn P, van der Bol JM, Verweij J, Sleijfer S, Loos WJ PMID: 21602518 [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=4876592 Thu, 19 May 2011 23:00:00 +0100 4876592 http://www.medworm.com/index.php?rid=4876591&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%3D21602519%26dopt%3DAbstract Authors: De Luca D, Minucci A, Trias J, Tripodi D, Conti G, Zuppi C, Capoluongo E Secretory phospholipase A2 (sPLA2), which links surfactant catabolism and lung inflammation, is associated with lung stiffness, surfactant dysfunction, and degree of respiratory support in acute respiratory distress syndrome and in some forms of neonatal lung injury. Varespladib potently inhibits sPLA2 in animal models. The authors investigate varespladib ex vivo efficacy in different forms of neonatal lung injury. Bronchoalveolar lavage fluid was obtained from 40 neonates affected by hyaline membrane disease, infections, or meconium aspiration and divided in 4 aliquots added with increasing varespladib or saline. sPLA2 activity, proteins, and albumin were measured. Dilution was corrected with the urea ra... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4876591 Thu, 19 May 2011 23:00:00 +0100 4876591 http://www.medworm.com/index.php?rid=4876598&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%3D21593279%26dopt%3DAbstract Authors: Darbà J, Restovic G, Kaskens L, Agustín TD The aim of this study was to determine health care resource utilization and direct medical costs in Spanish patients treated with intravenous immunoglobulins (IVIGs) in 2009. Cost-of-illness analyses were performed to estimate direct medical costs of patients treated with IVIGs. Prevalence data were obtained from the Spanish Primary Immunodeficiency registry. A semi-structured questionnaire was used to collect data on health care resource utilization and patient distribution. Drug, administration, and premedication costs were considered from the payer's perspective. Separate analyses were conducted for children and adolescents versus adults. The numbers of children and adolescents with replacement therapy were 724, with immunomodula... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4876598 Tue, 17 May 2011 23:00:00 +0100 4876598 http://www.medworm.com/index.php?rid=4876597&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%3D21593280%26dopt%3DAbstract Authors: Cho H, Choi MK, Cho DY, Yeo CW, Jeong HE, Shon JH, Lee JY, Shin JS, Cho M, Kim DY, Shin JG It is well known that the CYP2C19 genetic polymorphism influences the pharmacokinetics and pharmacodynamics of proton pump inhibitors (PPIs), but no report has addressed the effects on ilaprazole, a newly developed PPI. To investigate the effects of the CYP2C19 genetic polymorphism on the disposition and pharmacodynamics of ilaprazole, multiple doses of once-daily 10 mg ilaprazole were repeatedly administered for 7 days to 27 healthy Korean participants, comprising 9 homozygous CYP2C19 extensive metabolizers (homo EMs), 10 heterozygous EMs (hetero EMs), and 8 homozygous poor metabolizers (PMs). The plasma concentration and pharmacodynamic response were measured in the last dose interval.... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4876597 Tue, 17 May 2011 23:00:00 +0100 4876597 http://www.medworm.com/index.php?rid=4876596&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%3D21593281%26dopt%3DAbstract In conclusion, much improvement remains to be made in the quality of reporting of CTs to allow reliable quality assessment of published trials. PMID: 21593281 [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=4876596 Tue, 17 May 2011 23:00:00 +0100 4876596 http://www.medworm.com/index.php?rid=4876595&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%3D21593282%26dopt%3DAbstract Authors: Johnson FK, Ciric S, Boudriau S, Kisicki J, Stauffer J Although contraindicated, coingestion of alcohol and opioids by patients or drug abusers is a major health concern because of dangerous additive and potentially life-threatening sedative and respiratory effects. In addition, alcohol has been shown to disrupt the extended-release characteristics of certain extended-release opioid formulaions, releasing a hazardous amount of opioid over a short time period. Morphine sulfate and naltrexone hydrochloride extended release capsules (MS-sNT), which contain naltrexone sequestered in each pellet core, are indicated for management of chronic, moderate to severe pain. Sequestered naltrexone is designed for release upon product tampering (crushing) to potentially mitigate morphine-ind... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4876595 Tue, 17 May 2011 23:00:00 +0100 4876595 http://www.medworm.com/index.php?rid=4876594&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%3D21593283%26dopt%3DAbstract Authors: Ieiri I, Doi Y, Maeda K, Sasaki T, Kimura M, Hirota T, Chiyoda T, Miyagawa M, Irie S, Iwasaki K, Sugiyama Y The authors evaluated the contribution of the SLCO2B1 polymorphism to the pharmacokinetics of celiprolol at a microdose (MD) and therapeutic dose (TD) and compared pharmacokinetic proportionality between the 2 dose forms in 30 SLCO2B1 genotype-matched healthy volunteers. Three drugs (celiprolol, fexofenadine, and atenolol) were orally administered as a cassette dosing following the MD (totally 97.5 μg) and then a TD (100 mg) of celiprolol, with and without grapefruit juice. The mean AUC(0-24) of celiprolol was lower in SLCO2B1*3/*3 individuals (775 ng·h/mL) than in *1/*3 (1097 ng·h/mL) and *1/*1 (1547 ng·h/mL) individuals following the TD, and this was confirmed in p... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4876594 Tue, 17 May 2011 23:00:00 +0100 4876594 http://www.medworm.com/index.php?rid=4823680&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%3D21566199%26dopt%3DAbstract This study investigated the safety, pharmacokinetics, and pharmacodynamics of single oral doses of R1663, a factor Xa inhibitor, in healthy volunteers. It was a single-blind, randomized, crossover, placebo-controlled, dose escalation study in 33 healthy male volunteers aged 18 to 45 years. Each volunteer was dosed on 3 occasions with R1663 or placebo. Single oral doses of R1663 were safe and well tolerated. R1663 did not affect bleeding time. Pharmacodynamic effects (prothrombin time [PT], activated partial thromboplastin time [aPTT]), parameters of thrombogram, and anti-factor Xa activity) and plasma concentrations of R1663 were dose-dependent and showed low to moderate (<40%) inter-subject and intrasubject variability. Maximum factor Xa inhibition was achieved 3 hours post dose (time ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823680 Wed, 11 May 2011 23:00:00 +0100 4823680 http://www.medworm.com/index.php?rid=4823679&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%3D21566200%26dopt%3DAbstract Authors: Moberly JB, Rohatagi S, Zahir H, Hsu C, Noveck RJ, Truitt KE CS-0777 is a selective sphingosine 1-phosphate receptor-1 (S1P(1)) modulator under development for treatment of autoimmune conditions. A randomized, double-blind, placebo-controlled study was conducted to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of CS-0777 in escalating dose cohorts of healthy male participants (0.1, 0.3, 1.0, and 2.5 mg; 6 active, 2 placebo per cohort). Primary pharmacodynamic parameters were absolute lymphocyte counts and lymphocyte subsets (CD4 and CD8 T and B cells). CS-0777 resulted in a pronounced, dose-dependent decrease in absolute lymphocyte counts (mean percent decrease from baseline at 24 hours postdose: 7%, 26%, 52%, 79%, and 85%, for pl... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823679 Wed, 11 May 2011 23:00:00 +0100 4823679 http://www.medworm.com/index.php?rid=4823678&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%3D21566201%26dopt%3DAbstract Authors: Othman AA, Nothaft W, Awni WM, Dutta S ABT-102 is a selective TRPV1 antagonist with robust efficacy in several preclinical models of pain. Three phase 1 studies evaluated ABT-102 pharmacokinetics upon oral administration to healthy human volunteers: a single-dose study (2, 6, 18, 30, and 40 mg) and a multiple-dose study (2, 4, and 8 mg twice daily for 7 days) using a solution formulation and a multiple-dose study (1, 2, and 4 mg twice daily for 7 days) using a solid-dispersion formulation. These studies followed double-blind, randomized, placebo-controlled designs. ABT-102 exhibited dose- and time-linear pharmacokinetics. ABT-102 half-life ranged from 7 to 11 hours, and steady state was achieved by day 5 of dosing. Population analysis of the pharmacokinetic data from the 3 stu... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823678 Wed, 11 May 2011 23:00:00 +0100 4823678 http://www.medworm.com/index.php?rid=4823677&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%3D21566202%26dopt%3DAbstract This article aims to provide an overview of the current situation regarding pharmacogenetic and pharmacogenomic (PG) studies in pediatrics, with a special focus on the role of PG data in the regulatory decision-making process. Despite the gap in pharmacogenetic research due to the lack of translational studies in adults and children, several technologies exist in drug development and biomarkers validation, which could supply valuable information concerning labeling and dosing recommendations. If performed under strict good clinical practice quality criteria, such findings could be included in the submission package of new chemical entities and used as additional information for prescribers, supporting further evaluation and understanding of the efficacy and safety profile of new medicines.... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823677 Wed, 11 May 2011 23:00:00 +0100 4823677 http://www.medworm.com/index.php?rid=4823676&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%3D21566203%26dopt%3DAbstract Authors: Moore K, Zannikos P, Solanki B, Greenspan A, Verhaege T, Brashear HR This open-label, parallel-group study was designed to characterize the pharmacokinetics (PK) of carisbamate in participants with mild or moderate hepatic impairment versus those with normal hepatic function. Healthy (n = 10) and hepatic-impaired (n = 20) participants received a single 200-mg oral dose of carisbamate. Serial PK blood samples were collected up to 120 hours postdose. A modest increase in mean area under the plasma concentration-time curve from 0 to infinity (AUC(∞)) was observed for the mild impairment group compared with the normal group (ratio of geometric means ∼116%), while mean maximum plasma concentration (C(max)) values were similar (ratio of geometric means ∼94%). The AUC(∞) valu... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823676 Wed, 11 May 2011 23:00:00 +0100 4823676 http://www.medworm.com/index.php?rid=4823672&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%3D21566204%26dopt%3DAbstract This study explored potential underlying mechanisms in healthy male participants. Ten healthy male participants received in phenylephrine (PE)-preconstricted veins a dose-response curve (DRC) to L-NMMA (0.2-6.4 μmol/min) without and with coinfusion of the endothelium-dependent dilator histamine, a DRC to L-arginine with and without coinfusion of L-NMMA, a DRC to NG-monomethyl-D-arginine (D-NMMA), and a DRC to L-NMMA in prostaglandin F(2α)-(PGF(2α))-preconstricted veins. Participants were classified as L-NMMA responders (R) and nonresponders (NR). Infusion of L-NMMA resulted in a maximum venodilation of 38% ± 11% (R) versus 10% ± 5% (NR; P = .005). In PGF(2α)-preconstricted veins, L-NMMA caused venodilation to 26% ± 34% (NS) in responders. Results suggest that endothelial nitric oxid... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823672 Wed, 11 May 2011 23:00:00 +0100 4823672 http://www.medworm.com/index.php?rid=4823683&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%3D21558456%26dopt%3DAbstract Authors: Zhang X, Jordan P, Cristea L, Salgo M, Farha R, Kolis S, Lee LS The effect of saquinavir-boosted ritonavir at therapeutic (1000/100 mg twice daily [bid]) and supratherapeutic (1500/100 mg bid) doses was evaluated in a double-blind, placebo- and positive-controlled (moxifloxacin 400 mg) 4-way crossover thorough QT/QTc study. Least squares mean estimated study-specific QTc (QTcS) change from dense predose baseline (ddQTcS(dense)) was the primary endpoint. Greatest mean increase in ddQTcS(dense) occurred 12 hours postdose for the 1000/100-mg group (18.9 ms) and 20 hours for the 1500/10-mg group (30.2 ms). The upper 1-sided 95% confidence interval was >20 ms from 2 to 20 hours postdose in both groups. ddQTcB(dense) and ddQTcF(dense) were similar to ddQTcS(dense). No QTcS, QTcF,... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823683 Mon, 09 May 2011 23:00:00 +0100 4823683 http://www.medworm.com/index.php?rid=4823681&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%3D21558457%26dopt%3DAbstract Authors: Zhu R, Kiser JJ, Seifart HI, Werely CJ, Mitchell CD, D'Argenio DZ, Fletcher CV The roles of the NAT2 genotype and enzyme maturation on isoniazid pharmacokinetics were investigated in South African infants with perinatal HIV exposure enrolled in a randomized, double-blind, controlled trial of isoniazid for prevention of tuberculosis disease and latent infection. Plasma concentration-time measurements of isoniazid from 151 infants (starting at 3-4 months of age) receiving isoniazid 10 to 20 mg/kg/d orally during the course of the 24-month study were incorporated in a population analysis along with NAT2 genotype, body weight, age, and sex. The results showed a different NAT2 enzyme maturation profile for each of the 3 acetylation groups, with the 70-kg body weight-normalized typi... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823681 Mon, 09 May 2011 23:00:00 +0100 4823681 http://www.medworm.com/index.php?rid=4823723&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%3D21551316%26dopt%3DAbstract Authors: Riggs MM, Bergsma TT, Rogers JA, Gastonguay MR, Subramanian GM, Chen C, Devalaraja M, Corey AE, Sun H, Yu J, Stein DS Albinterferon alfa-2b (albIFN) has been studied for treatment of chronic hepatitis C virus (HCV). A population pharmacokinetics model was developed using nonlinear mixed-effects modeling. Efficacy/safety exposure-response relationships were assessed for subcutaneous albIFN doses (900-1800 μg once every 2 or 4 weeks) administered for either 24 weeks (HCV genotypes 2/3) or 48 weeks (genotype 1), plus daily oral ribavirin. Sustained virologic response (SVR) exposure-response was modeled using logistic regression. Adverse event incidence was tabulated versus exposure quartiles. First-order absorption rate constant (0.0148 h(-1)), apparent clearance (38.9 mL/h), an... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823723 Thu, 05 May 2011 23:00:00 +0100 4823723 http://www.medworm.com/index.php?rid=4823689&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%3D21551317%26dopt%3DAbstract In conclusion, propiverine ER has higher bioavailability than IR and no positive food effect because it reaches, independently of food, intestinal absorption areas with lower metabolism and efflux transport, which results in constant absorption rates. PMID: 21551317 [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=4823689 Thu, 05 May 2011 23:00:00 +0100 4823689 http://www.medworm.com/index.php?rid=4823684&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%3D21551318%26dopt%3DAbstract The objective of the study was to develop a population pharmacodynamic model describing the relationship between serum concentrations of lanreotide (C(P)) and its GH and IGF-1 effects in patients with acromegaly receiving lanreotide Autogel (LA) at doses of 60, 90, or 120 mg by deep subcutaneous route every 28 days. Data were analyzed from 104 patients. The GH and IGF-1 profiles were fit simultaneously using the population approach with NONMEM. The GH vs C(P) and the IGF-1 vs GH relationships were described using inhibitory I(max) and E(max) models, respectively. Results indicated that lanreotide cannot abolish GH completely. C(P) levels of 3.4 ng/mL are required to achieve percentages of hormonal control (GH and IGF-1) of 21% and 36% in not treated and previously treated patients. If the ... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823684 Thu, 05 May 2011 23:00:00 +0100 4823684 http://www.medworm.com/index.php?rid=4823736&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%3D21543662%26dopt%3DAbstract Authors: Matsui A, Azuma J, Witcher JW, Long AJ, Sauer JM, Smith BP, Desante KA, Read HA, Takahashi M, Nakano M Atomoxetine is a cytochrome P4502D6 (CYP2D6) substrate. The reduced-activity CYP2D6*10 allele is particularly prevalent in the Japanese population and may contribute to known ethnic differences in CYP2D6 metabolic capacity. The purpose of this study was to examine atomoxetine pharmacokinetics, safety, tolerability, and the effect of the CYP2D6*10/*10 genotype after single-stepped dosing (10, 40, 90, or 120 mg) and at steady state (40 or 60 mg twice a day for 7 days) in 49 healthy Japanese adult men. Dose proportionality was shown and tolerability confirmed at all doses studied. Comparison of pharmacokinetics, safety, and tolerability between Japanese and US subjects showed no... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823736 Tue, 03 May 2011 23:00:00 +0100 4823736 http://www.medworm.com/index.php?rid=4823735&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%3D21543663%26dopt%3DAbstract Authors: Ghosh RK, Ghosh SM, Chawla S, Jasdanwala SA The incidence of type 2 diabetes mellitus is increasing worldwide. The existing therapeutic classes of antidiabetic drugs are not adequately effective in maintaining long-term glycemic control in most patients, even when used in combination. One emerging novel therapeutic class of antidiabetic drugs is sodium glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 accounts for 90% of the glucose reabsorption in the kidney. The SGLT2 inhibitors increase urinary excretion of glucose and lower plasma glucose levels in an insulin-independent manner. Dapagliflozin, the most prominent molecule in this class, is currently in a phase III clinical trial. Other members of this class (eg, sergliflozin, remogliflozin) are also in different phases of c... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823735 Tue, 03 May 2011 23:00:00 +0100 4823735 http://www.medworm.com/index.php?rid=4823734&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%3D21543664%26dopt%3DAbstract Authors: Hennig S, Nyberg J, Fanta S, Backman JT, Hoppu K, Hooker AC, Karlsson MO A time and sampling intensive pretransplant test dose design was to be reduced, but at the same time optimized so that there was no loss in the precision of predicting the individual pharmacokinetic (PK) estimates of posttransplant dosing. The following variables were optimized simultaneously: sampling times, ciclosporin dose, time of second dose, infusion duration, and administration order, using a published ciclosporin population PK model as prior information. The original design was reduced from 22 samples to 6 samples/patient and both doses (intravenous oral) were administered within 8 hours. Compared with the prior information given by the published ciclosporin population PK model, the expected stand... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823734 Tue, 03 May 2011 23:00:00 +0100 4823734 http://www.medworm.com/index.php?rid=4823738&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%3D21525394%26dopt%3DAbstract Authors: Nolin TD, Arya V, Sitar DS, Pfister M PMID: 21525394 [PubMed - in process] (Source: The Journal of Clinical Pharmacology) The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823738 Sat, 30 Apr 2011 23:00:00 +0100 4823738 http://www.medworm.com/index.php?rid=4823737&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%3D21527400%26dopt%3DAbstract Authors: Jamali F PMID: 21527400 [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=4823737 Wed, 27 Apr 2011 23:00:00 +0100 4823737 http://www.medworm.com/index.php?rid=4823740&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%3D21508179%26dopt%3DAbstract Authors: Erdeve O, Atasay B, Arsan S, Türmen T PMID: 21508179 [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=4823740 Tue, 19 Apr 2011 23:00:00 +0100 4823740 http://www.medworm.com/index.php?rid=4823739&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%3D21508180%26dopt%3DAbstract Authors: O'Hara GE, Philippon F, Gilbert M, Champagne J, Michaud V, Charbonneau L, Pruneau G, Hamelin BA, Geelen P, Turgeon J Propafenone and its 5-hydroxy metabolite exhibit different electrophysiological properties. Objectives of the CAQ-PAF study were (1) to develop a strategy favoring propafenone instead of 5-hydroxypropafenone in plasma following oral administration of propafenone and (2) to evaluate the potential of low-dose quinidine to chronically inhibit CYP2D6. Patients (n = 102) with atrial fibrillation received propafenone 150 mg 3 times daily with either quinidine 100 mg twice daily or placebo. Throughout the study (follow-up, 199 ± 155 days), quinidine successfully inhibited CYP2D6: propafenone concentrations were 3 times higher in patients receiving quinidine (1033 ± 6... The Journal of Clinical Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823739 Tue, 19 Apr 2011 23:00:00 +0100 4823739