Interference in a Neutralizing Antibody Assay for Odronextamab, a CD20xCD3 Bispecific mAb, from Prior Rituximab Therapy and Possible Mitigation Strategy
AbstractA cell-based assay was developed to detect neutralizing anti-drug antibodies (NAbs) against odronextamab, a CD20xCD3 bispecific monoclonal antibody (mAb) under investigation for treatment of CD20+ B cell malignancies. In this assay, odronextamab bridges between two cell types, CD20-expressing HEK293 cells and CD3-expressing Jurkat T cells that generate a luciferase signal upon CD3 clustering. Patient samples containing NAbs directed to either arm of the bispecific drug block the odronextamab bridge formation between the cell lines thus preventing the generation of the luciferase signal. We determined that other ant...
Source: The AAPS Journal - June 21, 2022 Category: Drugs & Pharmacology Source Type: research
Capillary-Mediated Vitrification: Preservation of mRNA at Elevated Temperatures
In conclusion, CMV is a si mple formulation method that significantly enhances the thermal stability of mRNA, requires minimal processing time, and could enable formulation of mRNA that can tolerate exposure to temperatures well above 25 °C during shipment and deployment in extreme environments.Graphical abstract (Source: The AAPS Journal)
Source: The AAPS Journal - June 16, 2022 Category: Drugs & Pharmacology Source Type: research
Application of Artificial Neural Networks in the Process Analytical Technology of Pharmaceutical Manufacturing —a Review
AbstractIndustry 4.0 has started to transform the manufacturing industries by embracing digitalization, automation, and big data, aiming for interconnected systems, autonomous decisions, and smart factories. Machine learning techniques, such as artificial neural networks (ANN), have emerged as potent tools to address the related computational tasks. These advancements have also reached the pharmaceutical industry, where the Process Analytical Technology (PAT) initiative has already paved the way for the real-time analysis of the processes and the science- and risk-based flexible production. This paper aims to assess the po...
Source: The AAPS Journal - June 14, 2022 Category: Drugs & Pharmacology Source Type: research
Joint Disposition Properties and Comprehensive Pharmacokinetic Characterization of Antibody –Drug Conjugates
AbstractAntibody –drug conjugates (ADCs) comprise 3 distinct parts: a specific antibody carrier (mAb), a linker, and a cytotoxic payload. Typical pharmacokinetic (PK) characterization of ADCs remains fragmented using separate noncompartmental analyses (NCA) of individual analytes, offering little insight into the dynamic relationships among the ADC components, and the safety and efficacy implications. As a result, it is exceedingly difficult to compare ADCs in terms of favorable PK characteristics. Therefore, there is a need for characterizing ADCs using the joint disposition properties critical for understa nding the fa...
Source: The AAPS Journal - June 10, 2022 Category: Drugs & Pharmacology Source Type: research
Opportunities and Challenges for PBPK Model of mAbs in Paediatrics and Pregnancy
AbstractNew drugs may in some cases need to be tested in paediatric and pregnant patients. However, it is difficult to recruit such patients and there are many ethical issues around their inclusion in clinical trials. Modelling and simulation can help to plan well-designed clinical trials with a reduced number of participants and to bridge gaps where recruitment is difficult. Physiologically based pharmacokinetic (PBPK) models for small molecule drugs have been used to aid study design and dose adjustments in paediatrics and pregnancy, with several publications in the literature. However, published PBPK models for monoclon...
Source: The AAPS Journal - June 1, 2022 Category: Drugs & Pharmacology Source Type: research
Significance of the Vitamin D Receptor on Crosstalk with Nuclear Receptors and Regulation of Enzymes and Transporters
AbstractThe vitamin D receptor (VDR), in addition to other nuclear receptors, the pregnane X receptor (PXR) and constitutive androstane receptor (CAR), is involved in the regulation of enzymes, transporters and receptors, and therefore intimately affects drug disposition, tissue health, and the handling of endogenous and exogenous compounds. This review examines the role of 1 α,25-dihydroxyvitamin D3 or calcitriol, the natural VDR ligand, on activation of the VDR and its crosstalk with other nuclear receptors towards the regulation of enzymes and transporters, notably many of the cytochrome P450s including CYP3A4 and sulf...
Source: The AAPS Journal - June 1, 2022 Category: Drugs & Pharmacology Source Type: research
Selection of Payloads for Antibody –Drug Conjugates Targeting Ubiquitously Expressed Tumor-Associated Antigens: a Case Study
In conclusion, SY02-DXd demonstrated superior efficacy and safety with the widest therapeutic window. Based on the efficacy and safety results, moderate cytotoxic payloads would be ideal choices for ADCs targeting ubiquitously expressed antigens.Graphical Abstract (Source: The AAPS Journal)
Source: The AAPS Journal - May 27, 2022 Category: Drugs & Pharmacology Source Type: research
Correction: Effect of the Size of Protein Therapeutics on Brain Pharmacokinetics Following Systematic Administration
(Source: The AAPS Journal)
Source: The AAPS Journal - May 24, 2022 Category: Drugs & Pharmacology Source Type: research
When to Extend Monitoring of Anti-drug Antibodies for High-risk Biotherapeutics in Clinical Trials: an Opinion from the European Immunogenicity Platform
AbstractThe determination of a tailored anti-drug antibody (ADA) testing strategy is based on the immunogenicity risk assessment to allow a correlation of ADAs with changes to pharmacokinetics, efficacy, and safety. The clinical impact of ADA formation refines the immunogenicity risk assessment and defines appropriate risk mitigation strategies. Health agencies request for high-risk biotherapeutics to extend ADA monitoring for patients that developed an ADA response to the drug until ADAs return to baseline levels. However, there is no common understanding in which cases an extension of ADA follow-up sampling beyond the en...
Source: The AAPS Journal - May 12, 2022 Category: Drugs & Pharmacology Source Type: research
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
