Physiologically based pharmacokinetic modeling in regulatory decision‐making at the European Medicines Agency

Abstract

Physiologically based pharmacokinetic (PBPK) modeling is a valuable tool in drug development and regulatory assessment, as it offers the opportunity to simulate the pharmacokinetics of a compound, with a mechanistic understanding, in a variety of populations and situations. This work reviews the use and impact of such modeling in selected regulatory procedures submitted to the European Medicines Agency (EMA) before the end of 2015, together with its subsequent reflection in public documents relating to the assessment of these procedures. It is apparent that the reference to PBPK modeling in regulatory public documents underrepresents its use. A positive trend over time of the number of PBPK models submitted is shown, and in a number of cases the results of these may impact the decision-making process or lead to recommendations in the product labeling. These results confirm the need for regulatory guidance in this field, which is currently under development by the EMA.

Prediction of olanzapine exposure in individual patients using physiologically based pharmacokinetic modelling and simulation

“…The last 15 years have seen a dramatic increase in PBPK M&S to support drug applications to regulatory agencies . Approximately two‐thirds of studies are for predicting potential PK‐DDIs, which can mitigate the need for clinical studies .…”

“…These data are proof-ofconcept for MIPD after repurposing a widely available PBPK M&S platform. The last 15 years have seen a dramatic increase in PBPK M&S to support drug applications to regulatory agencies [48,49]. Approximately two-thirds of studies are for predicting potential PK-DDIs, which can mitigate the need for clinical studies [9,49,50].…”

Drug Dosing in Pregnant Women: Challenges and Opportunities in Using Physiologically Based Pharmacokinetic Modeling and Simulations

“…PBPK modeling and simulation offers a viable alternative to clinical trials for this vulnerable patient population. Regulatory agencies, such as the FDA and the European Medicines Agency, have adopted PBPK modeling and simulation to facilitate the review of Investigational New Drug and New Drug Application submissions to address a variety of clinical issues, including the assessment of the effect of intrinsic or extrinsic factors on drug PKs . In these applications, PBPK modeling is primarily used to facilitate the decision making process on whether, when, and how to conduct a clinical pharmacology study, and, more importantly, to inform drug labeling to support dosing recommendations .…”

Toward Dynamic Prescribing Information: Codevelopment of Companion Model‐Informed Precision Dosing Tools in Drug Development

“…The tool kit of quantitative approaches for MIDD has been described previously and includes PBPK modeling and simulation (M&S) . Over the last decade there has been a steady increase in PBPK models to support new drug applications to the U.S. FDA, the European Medicines Agency, and the Japanese Pharmaceuticals and Medical Devices Agency . Guidelines for PBPK models are now available to improve the quality and consistency of applications by pharmaceutical companies to regulators .…”