AAPS 2020 PharmSci 360

Certara will conduct a panel discussion with CDISC subject matter experts on challenges and best practices when preparing PK CDISC domains required for regulatory submissions to the US FDA.

PBPK models, informed by the prior knowledge of human anatomy, physiology, genetics and its associated variability, provides a robust framework to integrate physiochemical properties of drug substance and formulation quality attributes, thereby enabling understanding of complex interplay of drug/drug products and human physiology. Application of these (semi)-mechanistic models in the field of locally acting drug products is particularly interesting wherein drug concentrations at the local (action) site (hardly accessible via traditional experimentation) can be related to the therapeutic performance. This talk will discuss the considerations/key parameters needed to develop and verify/validate a mechanistic dermal absorption model (as implemented in Simcyp Simulator V19) capable of explaining observed in vitro and in vivo permeation of drugs across skin from topical applied drug products. The talk will highlight a case study discussing the application of PBPK model, verified with in vitro skin permeation, to predict in vivo exposure of topically applied drug products.

Clinical pharmacology spans all phases of drug development, and accounts for a substantial proportion of a drug product label. An important goal of drug development programs is to ensure sufficient characterization of the clinical pharmacology of the drug. The clinical pharmacology development strategy therefore needs to take into account both the intrinsic and extrinsic factors that alter drug exposure. Furthermore, the clinical pharmacology development strategy must meet the regulatory requirements of multiple health authorities in order to secure a global product registration. The presentation will highlight the challenges in developing an appropriate clinical pharmacology development strategy in order to establish the right dose for the right patient. An overview of the clinical pharmacology studies required to meet regulatory requirements will be presented including the timing of studies and how the incorporation of quantitative methodologies can help to facilitate dose selection. Examples of how the information generated in a clinical pharmacology program could impact global product labeling will be presented in the context of global regulatory requirements.

The clinical development of novel biotherapeutic modalities faces many challenges, including selection of relevant starting doses and prediction of efficacious dose. Multiple factors can contribute to variability in the clinic including differences in functional affinity due to avidity, receptor expression, effector to target cell ratio and presence of soluble target. Mechanistic modeling approaches are a powerful integrative tool to understand the complexities and aid in clinical translation, trial design and prediction of regimens and strategies to reduce dose limiting toxicities of innovative biologicals.

This roundtable will provide an introduction to the development of pediatric drug formulations and a case study demonstrating the use of PBPK modeling to advance a pediatric drug program.

The role of model informed drug development practices as applied to COVID will be discussed. It will include commentary on the application of viral cell cycle models, epidemiological models, health economic models to guide treatment considerations. It will also include consideration of PKPD assumptions, the application of physiological based PK modelling, model based metanalyses and how insights derived from model based methods can inform clinical trial design, individual and combination treatment and regimen selection for COVID-19, timing of intervention within the disease course, likely impact on individual versus population health goals.