Pharmacokinetic Models for Inhaled Fluticasone Propionate and Salmeterol Xinafoate to Quantify Batch-to-Batch Variability
AbstractAdvair Diskus is an essential treatment for asthma and chronic obstructive pulmonary disease. It is a dry powder inhaler with a combination of fluticasone propionate (FP) and salmeterol xinafoate (SX). However, the pharmacokinetics (PK) batch-to-batch variability of the reference-listed drug (RLD) hindered its generic product development. This work developed the PK models for inhaled FP and SX that could represent potential batch variability. Two batches each of the reference and the test product (R1,R2,T1,T2) of Advair Diskus (100 μg FP/50 μg SX inhalation) were administered to 60 healthy subjects in a 4-peri...
Source: The AAPS Journal - April 26, 2024 Category: Drugs & Pharmacology Source Type: research
Effect of Food Composition on the PK of Isoniazid Quantitatively Explained Using Physiologically Based Biopharmaceutics Modeling
AbstractThis work shows the utilization of a physiologically based biopharmaceutics model (PBBM) to mechanistically explain the impact of diverse food types on the pharmacokinetics (PK) of isoniazid (INH) and acetyl-isoniazid (Ac-INH). The model was established and validated using published PK profiles for INH along with a combination of measured and predicted values for the physico-chemical and biopharmaceutical propertied of INH and Ac-INH. A dedicated ontogeny model was developed for N-acetyltransferase 2 (NAT2) in human integrating Michaelis Menten parameters for this enzyme in the physiologically based pharmacokinetic...
Source: The AAPS Journal - April 24, 2024 Category: Drugs & Pharmacology Source Type: research
Application of Advanced Modeling Approaches Supporting Generic Product Development Under GDUFA for Fiscal Year 2023
(Source: The AAPS Journal)
Source: The AAPS Journal - April 24, 2024 Category: Drugs & Pharmacology Source Type: research
Third Generation Solid Dispersion-Based Formulation of Novel Anti-Tubercular Agent Exhibited Improvement in Solubility, Dissolution and Biological Activity
AbstractThe long treatment period and development of drug resistance in tuberculosis (TB) necessitates the discovery of new anti-tubercular agents. The drug discovery program of the institute leads to the development of an anti-tubercular lead (IIIM-019), which is an analogue of nitrodihydroimidazooxazole and exhibited promising anti-tubercular action. However, IIIM-019 displays poor aqueous solubility (1.2 µg/mL), which demands suitable dosage form for its efficient oral administration. In the present study, third generation solid dispersion-based formulation was developed to increase the solubility and dissolution of ...
Source: The AAPS Journal - April 22, 2024 Category: Drugs & Pharmacology Source Type: research
Implementation of a Three-Way Comparability Assessment for a Bioanalytical Anti-Drug Antibody Method
AbstractImmunogenicity evaluation is a critical part of drug development. Regulatory guidelines from multiple health agencies provide recommendations for the development and validation of anti-drug antibody (ADA) assays to assess immunogenicity in clinical trials. These recommendations primarily describe an ADA method run in one bioanalytical laboratory supporting a biotherapeutic molecule; however, there are increasing instances that may necessitate the support of the ADA method being run in more than one laboratory. A program can rapidly expand into multiple clinical studies within one or multiple countries, where the mo...
Source: The AAPS Journal - April 18, 2024 Category: Drugs & Pharmacology Source Type: research
Group-by-Treatment Interaction Effects in Comparative Bioavailability Studies
AbstractComparative bioavailability studies often involve multiple groups of subjects for a variety of reasons, such as clinical capacity limitations. This raises questions about the validity of pooling data from these groups in the statistical analysis and whether a group-by-treatment interaction should be evaluated. We investigated the presence or absence of group-by-treatment interactions through both simulation techniques and a meta-study of well-controlled trials. Our findings reveal that the test falsely detects an interaction when no true group-by-treatment interaction exists. Conversely, when a true group-by-treatm...
Source: The AAPS Journal - April 17, 2024 Category: Drugs & Pharmacology Source Type: research
Ginsenoside Rg1 Alleviates Sepsis-Induced Acute Lung Injury by Reducing FBXO3 Stability in an m6A-Dependent Manner to Activate PGC-1 α/Nrf2 Signaling Pathway
ConclusionRg1 activated PGC-1 α/Nrf2 signaling pathway by reducing FBXO3 stability in an m6A-YTHDF1-dependent manner to improve mitochondrial function in lung epithelial cells during sepsis-induced ALI progression.Graphical Abstract (Source: The AAPS Journal)
Source: The AAPS Journal - April 15, 2024 Category: Drugs & Pharmacology Source Type: research
Preliminary Investigation of a Rapid and Feasible Therapeutic Drug Monitoring Method for the Real-Time Estimation of Blood Pazopanib Concentrations
AbstractPazopanib is a multi-kinase inhibitor used to treat advanced/metastatic renal cell carcinoma and advanced soft tissue tumors; however, side effects such as diarrhea and hypertension have been reported, and dosage adjustment based on drug concentration in the blood is necessary. However, measuring pazopanib concentrations in blood using the existing methods is time-consuming; and current dosage adjustments are made using the results of blood samples taken at the patient's previous hospital visit (approximately a month prior). If the concentration of pazopanib could be measured during the waiting period for a doctor ...
Source: The AAPS Journal - April 15, 2024 Category: Drugs & Pharmacology Source Type: research
Recent Advances in Drug Delivery
(Source: The AAPS Journal)
Source: The AAPS Journal - April 15, 2024 Category: Drugs & Pharmacology Source Type: research
Bile Acid –Targeted Hyaluronic Acid Nanoparticles for Enhanced Oral Absorption of Deferoxamine
AbstractPatients with β-thalassemia and sickle cell disease often rely on blood transfusions which can lead to hemochromatosis and chronic oxidative stress in cells and tissues. Deferoxamine (DFO) is clinically approved to treat hemochromatosis but is suboptimal to patients due to its poor pharmacokinetics which require s long-term infusion regimens. Although the oral route is preferable, DFO has limited oral bioavailability. Studies have shown that hyaluronic acid (HA) and bile acid (BA) can enhance the oral absorption of poorly absorbed drugs. To improve upon the oral delivery of DFO, we report on the synthesis a nd cha...
Source: The AAPS Journal - April 12, 2024 Category: Drugs & Pharmacology Source Type: research
Leveraging Modeling and Simulation to Enhance the Efficiency of Bioequivalence Approaches for Generic Drugs: Highlights from the 2023 Generic Drug Science and Research Initiatives Public Workshop
AbstractThe 2023 Generic Drug Science and Research Initiative Public Workshop organized by the U.S. Food and Drug Administration (FDA) discussed the research needs to improve and enhance bioequivalence (BE) approaches for generic drug development. FDA takes such research needs and panel discussions into account to develop its Generic Drug User Fee Amendments III (GDUFA III) Science and Research Initiatives specific to generics. During the five workshop sessions, presentations and panel discussions focused on identifying and addressing scientific gaps and research needs related to nitrosamine impurity issues, BE assessment ...
Source: The AAPS Journal - April 8, 2024 Category: Drugs & Pharmacology Source Type: research
Oral Drug Product Administration via Enteral Feeding Tubes: In Vitro Testing
AbstractMedication administrationvia enteral feeding tubes (EFT) is a necessary practice for patients unable to swallow oral dosage forms due to a medical condition or treatment that affects the ability to swallow or the function of the gastrointestinal tract. Off-label administration of oral drug productsvia EFT raises concerns for pharmaceutical sponsors, regulators, and healthcare practitioners (HCPs) because of the potential risks this practice introduces to both the patient and the caregiver. These risks can be mitigated by generating data-supported instructions that patients and HCPs can use to ensure safe and accura...
Source: The AAPS Journal - April 4, 2024 Category: Drugs & Pharmacology Source Type: research
Mechanistic Modeling of In Vitro Biopharmaceutic Data for a Weak Acid Drug: A Pathway Towards Deriving Fundamental Parameters for Physiologically Based Biopharmaceutic Modeling
The objective of this tutorial is to (1) review processes and parameters contributing to oral drug absorption in increasing levels of complexity, (2) outline a general physiologically based biopharmaceutic modeling workflow for weak acids, and (3) illustrate the outlined concepts via an ibuprofen (i.e., a weak, poorly soluble acid) case example in order to provide practical guidance on how to integrate biopharmaceutic and physiological data to better understand oral drug absorption. In the future, we plan to explore the usefulness of this tutorial/roadmap to inform the development of PBPK models for BCS 2 weak bases, by ex...
Source: The AAPS Journal - April 4, 2024 Category: Drugs & Pharmacology Source Type: research
Predicting the Stability of Lyophilized Human Serum Albumin Formulations Containing Sucrose and Trehalose Using Solid-State NMR Spectroscopy: Effect of Storage Temperature on 1H T1 Relaxation Times
AbstractIn a lyophilized protein/disaccharide system, the ability of the disaccharide to form a homogeneous mixture with the protein and to slow the protein mobility dictates the stabilization potential of the formulation. Human serum albumin was lyophilized with sucrose or trehalose in histidine, phosphate, or citrate buffer.1H T1 relaxation times were measured by solid-state NMR spectroscopy and were used to assess the homogeneity and mobility of the samples after zero, six, and twelve months at different temperatures. The mobility of the samples decreased after 6 and 12 months storage at elevated temperatures, consist...
Source: The AAPS Journal - April 3, 2024 Category: Drugs & Pharmacology Source Type: research
Cross-Reactive Polyclonal Antibodies Raised Against GalNAc-Conjugated siRNA Recognize Mostly the GalNAc Moiety
In this study, anti-siRNA polyclonal antibodies were generated through animal immunization. These cross-reactive polyclonal antibodies recognized mostly the N-acetylgalactosamine (GalNAc) moiety with a small fraction against sequence-independent epitopes. We demonstrate that the polyclonal antibodies can be utilized as immunogenicity assay positive controls for the same class of GalNAc-conjugated siRNAs. In addition, anti-GalNAc mAbs showed desired sensitivity and drug tolerance, supporting their use as alternative surrogate positive controls. These findings can guide positive control selection and immunogenicity assay dev...
Source: The AAPS Journal - April 3, 2024 Category: Drugs & Pharmacology Source Type: research
