Physiologically Based Pharmacokinetic Model Qualification and Reporting Procedures for Regulatory Submissions: A Consortium Perspective

Abstract

This work provides a perspective on the qualification and verification of physiologically based pharmacokinetic (PBPK) platforms/models intended for regulatory submission based on the collective experience of the Simcyp Consortium members. Examples of regulatory submission of PBPK analyses across various intended applications are presented and discussed. European Medicines Agency (EMA) and US Food and Drug Administration (FDA) recent draft guidelines regarding PBPK analyses and reporting are encouraging, and to advance the use and acceptability of PBPK analyses, more clarity and flexibility are warranted.

Figure 1

General components of a PBPK analysis package for submission to regulatory health authorities. Green frame represents the PBPK platform components that undergo qualification; blue frame represents the PBPK components that undergo verification. Model iteration is considered a verification step when new data emerge (i.e., clinical observations) and new learnings are applied to the drug model. The model iteration is an essential step towards verification of the parameters and assumptions that were originally implemented, including newly generated data to confirm prior assumptions and optimize parameters where necessary, a process that is generally accepted as good modeling practice across various areas of modeling and simulation.

Figure 2

Steps for qualification of virtual populations using PBPK modeling and simulation.

Figure 3

Rates of acceptance of PBPK analyses by the FDA or EMA among DDI and non‐DDI related submissions.