A General Biphasic Bodyweight Model for Scaling Basal Metabolic Rate, Glomerular Filtration Rate, and Drug Clearance from Birth to Adulthood
In conclusion, the proposed mixed-allo metry equation is a generic model that quantitatively describes the phase transition in the human maturation process of diverse human functions.Graphical Abstract (Source: The AAPS Journal)
Source: The AAPS Journal - May 10, 2022 Category: Drugs & Pharmacology Source Type: research
Biomarker Assay Validation by Mass Spectrometry
AbstractDecades of discussion and publication have gone into the guidance from the scientific community and the regulatory agencies on the use and validation of pharmacokinetic and toxicokinetic assays by chromatographic and ligand binding assays for the measurement of drugs and metabolites. These assay validations are well described in the FDA Guidance on Bioanalytical Methods Validation (BMV, 2018). While the BMV included biomarker assay validation, the focus was on understanding the challenges posed in validating biomarker assays and the importance of having reliable biomarker assays when used for regulatory submissions...
Source: The AAPS Journal - May 9, 2022 Category: Drugs & Pharmacology Source Type: research
Is Incurred Sample Reanalysis (ISR) Applicable in Biomarker Assays?
(Source: The AAPS Journal)
Source: The AAPS Journal - May 5, 2022 Category: Drugs & Pharmacology Source Type: research
A Critical Overview of the Biological Effects of Excipients (Part II): Scientific Considerations and Tools for Oral Product Development
AbstractIt is now recognized that a number of excipients previously considered to be “inert” have the capacity to alter drug oral bioavailability through a range ofin vivo effects. The various mechanisms through which an excipient can affectin vivo gastrointestinal physiology and drug absorption characteristics were explored in “A Critical Overview of The Biological Effects of Excipients (Part I): Impact on Gastrointestinal Absorption.” The next critical issue that needs to be discussed is how these biological effects are evaluated. Therefore, in Part 2 of this critical overview, thein vitro,in vivo, andin silico m...
Source: The AAPS Journal - May 2, 2022 Category: Drugs & Pharmacology Source Type: research
Application of Modeling and Simulation to Identify a Shortened Study Duration and Novel Bioequivalence Metric for a Long-Acting Intrauterine System
AbstractAn intrauterine system (IUS) can be implanted in the uterus and deliver drug directly at the site of pharmacological action. Mirena was the first FDA-approved levonorgestrel (LNG) releasing IUS without an approved generic form. Its 5-year application duration presents challenges for bioequivalence (BE) assessment using the conventionalin vivo studies with pharmacokinetic and/or comparative clinical endpoints. Conventionally, along with other conditions, BE could be established if the 90% confidence interval (CI) of the ratio of geometric means of residual LNG at the end of 5 years is within the BE limits of 80.00...
Source: The AAPS Journal - May 2, 2022 Category: Drugs & Pharmacology Source Type: research
A Critical Overview of the Biological Effects of Excipients (Part I): Impact on Gastrointestinal Absorption
AbstractTraditionally, excipients have been considered in drug development from the perspective of their influence on drug solubility, manufacturability, and ability to controlin vitro andin vivo drug release. These effects have been largely evaluated through studies involvingin vitro dissolution methods. However, there is a growing awareness that what had previously been considered biologically inert excipients can exert numerousin vivo effects. This includes the potential to change gastrointestinal (GI) transit time, enterocyte passive transcellular or paracellular permeability, active transport activity, or presystemic ...
Source: The AAPS Journal - May 2, 2022 Category: Drugs & Pharmacology Source Type: research
A Fit-for-Purpose Method to Measure Circulating Levels of the mRNA Component of a Liposomal-Formulated Individualized Neoantigen-Specific Therapy for Cancer
AbstractAutogene cevumeran is an individualized neoantigen-specific therapy (iNeST) under development for the treatment of various solid tumors. It consists of an RNA-Lipoplex (RNA-LPX) in which the encapsulated mRNA molecule encodes up to ten neoepitopes identified from each individual patient. In association with major histocompatibility complex (MHC) class I and MHC class II, these neoantigens can potentially stimulate and expand neoantigen-specific CD4+ and CD8+ T cells, leading to antitumor responses. As part of the pharmacokinetic (PK) property assessment of Autogene cevumeran in patients, both the lipid and mRNA con...
Source: The AAPS Journal - May 2, 2022 Category: Drugs & Pharmacology Source Type: research
Effect of the Size of Protein Therapeutics on Brain Pharmacokinetics Following Systematic Administration
AbstractHere, we have investigated the effect of size of protein therapeutics on brain pharmacokinetics (PK) following systemic administration in rats. All tested proteins were derived from trastuzumab that do not bind to any targets in rats. PK data generated with F(ab)2 (100 kDa), Fab (50 kDa), and scFv (27 kDa) fragments of trastuzumab, along with published PK data for FcRn non-binding and wild-type trastuzumab (150 kDa), were used to establish a relationship between the protein size and brain exposure. A large-pore microdialysis system was used to measure the PK of proteins in the plasma, the interstitial fluid ...
Source: The AAPS Journal - May 2, 2022 Category: Drugs & Pharmacology Source Type: research
Does Food Affect the Pharmacokinetics of Non-orally Delivered Drugs? A Review of Currently Available Evidence
AbstractThe food effects for orally administered drugs have been widely investigated and reviewed. In contrast, our knowledge of food effects for non-orally administered drugs is scarce. In this review paper, we did a literature survey to collect clinical food effect data for non-orally administered drugs. Our survey retrieved 18 drugs, including thirteen intravenously (IV), two subcutaneously (SC), one intradermally (ID), one pulmonary, and one rectally administered drug. The food effect data show that food intake can increase the absorption of SC and ID administered peptides and proteins with MW < 30 kDa by 30...
Source: The AAPS Journal - April 29, 2022 Category: Drugs & Pharmacology Source Type: research
Tumor Growth Inhibition-Overall Survival (TGI-OS) Model for Subgroup Analysis Based on Post-Randomization Factors: Application for Anti-drug Antibody (ADA) Subgroup Analysis of Atezolizumab in the IMpower150 Study
AbstractLongitudinal changes of tumor size or tumor-associated biomarkers have been receiving growing attention as early markers of treatment benefits. Tumor growth inhibition-overall survival (TGI-OS) models represent mathematical frameworks used to establish a link from tumor size trajectory to survival outcome with the aim of predicting survival benefit with tumor data from a small number of subjects with a short follow-up time. In the present study, we applied the TGI-OS model to assess treatment benefit in the IMpower150 study for patients who exhibited development of anti-drug antibodies (ADA). Direct comparison betw...
Source: The AAPS Journal - April 28, 2022 Category: Drugs & Pharmacology Source Type: research
Machine Learning Prediction of Clinical Trial Operational Efficiency
AbstractClinical trials are the gatekeepers and bottlenecks of progress in medicine. In recent years, they have become increasingly complex and expensive, driven by a growing number of stakeholders requiring more endpoints, more diverse patient populations, and a stringent regulatory environment. Trial designers have historically relied on investigator expertise and legacy norms established within sponsor companies to improve operational efficiency while achieving study goals. As such, data-driven forecasts of operational metrics can be a useful resource for trial design and planning. We develop a machine learning model to...
Source: The AAPS Journal - April 21, 2022 Category: Drugs & Pharmacology Source Type: research
International Regulatory Collaboration on the Analysis of Nitrosamines in Metformin-Containing Medicines
AbstractRecalls of some batches of metformin have occurred due to the detection ofN-nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng per day. Prior to the recalls, an international regulatory laboratory network had been monitoring drugs for nitrosamine impurities with each laboratory independently developing and validating multiple analytical procedures to detect and measure nitrosamines in metformin drugs used in their juri sdictions. Here, we provide an overview of the analysis of metformin active pharmaceutical ingredients (APIs) and drug products with 1090 samples (875 finished dosage ...
Source: The AAPS Journal - April 21, 2022 Category: Drugs & Pharmacology Source Type: research
Correction: Best Practices in qPCR and dPCR Validation in Regulated Bioanalytical Laboratories
(Source: The AAPS Journal)
Source: The AAPS Journal - April 19, 2022 Category: Drugs & Pharmacology Source Type: research
Dissolution profile similarity analyses —statistical principles, methods and considerations
AbstractThe pharmaceutical industry and regulatory agencies rely on dissolution similarity testing to make critical product decisions as part of drug product life cycle management. Accordingly, the application of mathematical approaches to evaluate dissolution profile similarity is described in regulatory guidance with the emphasis given to the similarity factorf2 with little discussion of alternative methods. In an effort to highlight current practices to assess dissolution profile similarity and to strive toward global harmonization, a workshop entitled “In Vitro Dissolution Similarity Assessment in Support of Drug Pro...
Source: The AAPS Journal - April 6, 2022 Category: Drugs & Pharmacology Source Type: research
A Model-Based Approach to Bridging Plasma and Dried Blood Spot Concentration Data for Phase 3 Verubecestat Trials
AbstractIn-clinic venous dried blood spot (DBS) pharmacokinetic (PK) sampling was incorporated into two phase 3 studies of verubecestat for Alzheimer ’s disease (EPOCH [NCT01739348] and APECS [NCT01953601]), as a potential alternative to plasma PK sampling. Initially, plasma and DBS PK samples were collected concurrently to better understand the DBS–plasma verubecestat concentration relationship, with the intention of discontinuing DBS or pla sma sampling following interim analysis. Following initial analyses and comparison of results with prespecified selection criteria, plasma PK sampling was discontinued; however, a...
Source: The AAPS Journal - April 6, 2022 Category: Drugs & Pharmacology Source Type: research
