A Novel Approach for Quantifying the Pharmacological Activity of T-Cell Engagers Utilizing In Vitro Time Course Experiments and Streamlined Data Analysis
AbstractCD3-bispecific antibodies are a new class of immunotherapeutic drugs against cancer. The pharmacological activity of CD3-bispecifics is typically assessed through in vitro assays of cancer cell lines co-cultured with human peripheral blood mononuclear cells (PBMCs). Assay results depend on experimental conditions such as incubation time and the effector-to-target cell ratio, which can hinder robust quantification of pharmacological activity. In order to overcome these limitations, we developed a new, holistic approach for quantification of the in vitro dose –response relationship. Our experimental design inte...
Source: The AAPS Journal - December 3, 2021 Category: Drugs & Pharmacology Source Type: research
Microfluidic-Generated Immunomodulatory Nanoparticles and Formulation-Dependent Effects on Lipopolysaccharide-Induced Macrophage Inflammation
AbstractNanoparticles (NPs) have emerged as a highly useful and clinically translatable drug delivery platform for vast therapeutic payloads. Through the precise tuning of their physicochemical properties, NPs can be engineered to exhibit controlled drug release properties, enhanced circulation times, improved cellular uptake and targeting, and reduced toxicity profiles. Conventional bulk methods for the production of polymeric NPs suffer from the ability to control their size and polydispersity, batch-to-batch variability, significant preparation times, and low recovery. Here, we describe the development and optimization ...
Source: The AAPS Journal - December 2, 2021 Category: Drugs & Pharmacology Source Type: research
Assessment of the Kochak-Benet Equation for Hepatic Clearance for the Parallel-Tube Model: Relevance of Classic Clearance Concepts in PK and PBPK
This report reviews concepts related to operation of the classic parallel-tube model (PTM) for hepatic disposition and examines two recent proposals of a newly derived equation to describe hepatic clearance (CLH). It is demonstrated that the proposed equation is identical to a re-arrangement of an earlier relationship from Pang and Rowland and provides a means of calculation of intrinsic clearance (CLint,PTM) rather thanCLH as posed. We further demonstrate how classic hepatic clearance models with an assumedCLint, while subject to numerous limitations, remain highly useful and necessary in both traditional pharmacokinetics...
Source: The AAPS Journal - December 1, 2021 Category: Drugs & Pharmacology Source Type: research
Anti-drug Antibody Validation Testing and Reporting Harmonization
AbstractEvolving immunogenicity assay performance expectations and a lack of harmonized anti-drug antibody validation testing and reporting tools have resulted in significant time spent by health authorities and sponsors on resolving filing queries. Following debate at the American Association of Pharmaceutical Sciences National Biotechnology Conference, a group was formed to address these gaps. Over the last 3 years, 44 members from 29 organizations (including 5 members from Europe and 10 members from FDA) discussed gaps in understanding immunogenicity assay requirements and have developed harmonization tools for use by...
Source: The AAPS Journal - December 1, 2021 Category: Drugs & Pharmacology Source Type: research
Innovative Design and Analysis for PK/PD Biosimilar Bridging Studies with Multiple References
AbstractWhen there are multiple reference products, (e.g., EU-approved product and US-licensed product), a pharmacokinetic/pharmacodynamic (PK/PD) bridging study is often conducted in order to bridge the clinical data from the original region (e.g., Europe) to the new region (e.g., USA) in support of the biosimilar regulatory submission in the new region. The purpose is to avoid duplicated clinical trials for clinical similarity between a proposed biosimilar product and the reference product in the new region provided that there is no ethnic concern in the two regions. In this article, some innovative statistical designs f...
Source: The AAPS Journal - November 30, 2021 Category: Drugs & Pharmacology Source Type: research
Navigating Through Cell-Based In vitro Models Available for Prediction of Intestinal Permeability and Metabolism: Are We Ready for 3D?
Abstract.Traditionally,in vitro studies to quantify the
intestinal permeability of drugs have relied on two-dimensional cell culture models using human colorectal carcinoma cell lines, namely Caco-2, HT 29 and T84 cells. Although these models have been commonly used for high-throughput screening of xenobiotics in preclinical studies, they do not fully recapitulate the morphology and functionality of enterocytes found in the human intestinein vivo. Efforts to improve the physiological and functional relevance ofin vitro intestinal models have led to the development of enteroids/intestinal organoids and microphysiologica...
Source: The AAPS Journal - November 22, 2021 Category: Drugs & Pharmacology Source Type: research
Correction to: Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate?
(Source: The AAPS Journal)
Source: The AAPS Journal - November 22, 2021 Category: Drugs & Pharmacology Source Type: research
Correction to: Considerations for Updates to ICH Q1 and Q5C Stability Guidelines: Embracing Current Technology and Risk Assessment Strategies
(Source: The AAPS Journal)
Source: The AAPS Journal - November 15, 2021 Category: Drugs & Pharmacology Source Type: research
ICH Q10 Pharmaceutical Quality System Guidance: Understanding Its Impact on Pharmaceutical Quality
This study evaluated the impact of the ICH Q10 guidance on the PQS of pharmaceutical manufacturers. Dat a were obtained from the enabler questionnaire from pharmaceutical manufacturers surveyed by the St. Gallen OPEX Benchmarking Program. These results represent the degree of implementation for enabler-focused questions based on a 5-point Likert scale self-assessment. Data analysis included a comparis on of means and medians before and after the release of the ICH Q10 guidance and annual changes. There was a statistically significant difference for enabler implementation as a whole (p value< 0.0000), before and after th...
Source: The AAPS Journal - November 12, 2021 Category: Drugs & Pharmacology Source Type: research
Pharmacokinetics of Monoclonal Antibody and Antibody Fragments in the Mouse Eye Following Systemic Administration
This study is the first of its kind to quantitatively measure the PK of variously sized proteins in the plasma, cornea/ICB, vitreous humor, retina, and posterior cup (including choroid) of the mouse and to evaluate the relationship between molecular weight (MW) and antibody biodistribution coefficient (BC) to the eye. Proteins analyzed include trastuzumab (150 kDa), trastuzumab-vc-MMAE (T-vc-MMAE, 155 kDa), F(ab)2 (100 kDa), Fab (50 kDa), and scFv (27 kDa). As expected, ocular PK mirrored the systemic PK as plasma was the driving force for ocular exposure. For trastuzumab, T-vc-MMAE, F(ab)2, Fab, and scFv, respectiv...
Source: The AAPS Journal - November 8, 2021 Category: Drugs & Pharmacology Source Type: research
Immunogenicity Risk Assessment for Multi-specific Therapeutics
The objective of this manuscript is to provide the reader with a hypothetical case study to present an immunogenicity risk assessment for a multi-specific therapeutic as part of Investigational New Drug (IND) application. In order to provide context for the bioanalytical strategies used to support the multi-specific therapeutic presented herein, the introduction focuses on known immunogenicity risk factors. The subsequent hypothetical case study applies these principles to a specific example HC-12, based loosely on anti-TNF α and anti-IL-17A bispecific molecules previously in development, structured as an example immunoge...
Source: The AAPS Journal - November 5, 2021 Category: Drugs & Pharmacology Source Type: research
Understanding Drug Delivery to the Brain Using Liposome-Based Strategies: Studies that Provide Mechanistic Insights Are Essential
AbstractBrain drug delivery may be restricted by the blood-brain barrier (BBB), and enhancement by liposome-based drug delivery strategies has been investigated. As access to the human brain is limited, many studies have been performed in experimental animals. Whereas providing interesting data, such studies have room for improvement to provide mechanistic insight into the rate and extent of specifically BBB transport and intrabrain distribution processes that all together govern CNS target delivery of the free drug. This review shortly summarizes BBB transport and current liposome-based strategies to overcome BBB transpor...
Source: The AAPS Journal - October 28, 2021 Category: Drugs & Pharmacology Source Type: research
Understanding In Vivo Dissolution of Immediate Release (IR) Solid Oral Drug Products Containing Weak Acid BCS Class 2 (BCS Class 2a) Drugs
In this study, nonsteroidal anti-inflammatory drugs (NSAIDs) are used to investigate thein vivo dissolution of BCS Class 2a drugs based on numerical deconvolution analyses. The PK data were obtained from published literature or drug applications submitted to the FDA. It has been hypothesized that thein vivo drug dissolution rate would likely correlate to the solubility of NSAIDs in the media at gastrointestinal pH. Our findings show a short lag time of absorption (Tlag), comparable to the liquid gastric emptying time and independent of the solubility and formulation.In Vivo drug dissolution of NSAIDs was generally rapid an...
Source: The AAPS Journal - October 26, 2021 Category: Drugs & Pharmacology Source Type: research
Understanding Quality Paradigm Shifts in the Evolving Pharmaceutical Landscape: Perspectives from the USP Quality Advisory Group
AbstractRecent changes in the pharmaceutical industry have led to significant paradigm shifts in the pharmaceutical quality environment. Globalization of the pharmaceutical
industry, increasingly rapid development of novel therapies, and adoption of new manufacturing techniques have presented numerous challenges for the established regulatory framework and quality environment and are impacting the approaches utilized to ensure the quality of pharmaceutical products. Regulators, industry, and standards-setting organizations have begun to recognize the need to rely more on integrated risk-based approaches and to create m...
Source: The AAPS Journal - October 15, 2021 Category: Drugs & Pharmacology Source Type: research
A Systematic Approach for Liposome and Lipodisk Preclinical Formulation Development by Microfluidic Technology
In this study, microfluidic techniques were employed to fabricate liposomes and lipodisks formulations allowing for a reproducible strategy for formulation development. Both liposome and lipodisk of curcumin demonstrated enhancedin vivo performance compared with a conventional formulation in the rat pharmacokinetic study. This combination of approaches with multiple model compounds and lipid-based drug delivery systems provides a systematic guidance to effective strategies to generate higher EE with minimal drug waste and expedite the process for preclinical development when applied to industry compounds. (Source: The AAPS Journal)
Source: The AAPS Journal - October 14, 2021 Category: Drugs & Pharmacology Source Type: research
