Best Practices in Physiologically Based Pharmacokinetic (PBPK) Modeling

PBPK & PBBM

Regulatory interactions

CPT: Pharmacometrics & Systems Pharmacology, 2026 July; 15(7)

Chenel M, Dallmann A, Ince I, Meyer M, Schlender JF, Teutonico D, Sjögren E.

While physiologically based pharmacokinetic (PBPK) modeling has become a mechanistic cornerstone of model-informed drug development, recent reviews by the EMA and other regulatory bodies show that a significant disparity in quality persists. Too often, submitted models are not deemed adequately qualified for their intended context of use.

How do we bridge this gap in quality between regulatory expectations and submitted PBPK analyses?

Published in CPT: Pharmacometrics & Systems Pharmacology, this collaborative new paper establishes a harmonized framework designed to improve the consistency, quality, and transparency of PBPK analyses, ultimately building greater regulatory confidence.

Key highlights:

Comprehensive best practices: Actionable guidance spanning the entire PBPK workflow, including planning, data compilation, model development, evaluation, and application.
Regulatory alignment: Direct harmonization of PBPK terminology and expectations with the ICH M15 guideline on MIDD.
Fit-for-purpose strategy: Practical framework to define explicit technical criteria, ensuring models are demonstrably qualified for their specific Context of Use (CoU).

This paper represents a truly collaborative effort across the industry, bringing together experts with a common goal to establish harmonized best practices: Marylore Chenel and Erik Sjögren from Pharmetheus, in collaboration with Andre Dallmann and Michaela Meyer from Bayer, Ibrahim Ince from Boehringer Ingelheim, Jan Schlender from Novartis and Donato Teutonico from Sanofi.

What is PBPK modeling?

Physiologically Based Pharmacokinetic (PBPK) modeling is a mechanistic approach that integrates physiological, drug-specific, and formulation data to simulate how a drug behaves within the body.
As a cornerstone of model-informed drug development, PBPK is used to predict drug behavior, informing critical decisions throughout the drug development lifecycle.

Key applications include

Supporting First-in-Human study design based on in  vitro with/without animal studies
Assessing drug-drug interactions (DDIs)
Predicting drug exposure in special populations, e.g., pediatric, geriatric, pregnant, obese or organ- impaired patients
Supporting formulation development and virtual bioequivalence

The regulatory challenge

Despite the mature history of PBPK modeling and its successful track record in regulatory submissions, recent regulatory reviews show a persistent quality gap: many submitted models fail to demonstrate fit-for-purpose qualification, leading to frequent rejections by health authorities.

Significant-gap-in-quality-pbpk-best-practices

While the new ICH M15 guideline establishes the conceptual relationship between decision risk and model credibility, PBPK model developers stand to benefit from a standard, practical roadmap to operationalize these expectations on a  day-to-day basis.

Bridging the gap – A fit-for-purpose framework

In this collaborative initiative, the authors present a structured and actionable sequential workflow, designed to:

Enhance the quality, consistency and regulatory acceptance of PBPK submissions
Harmonize terminology with ICH M15
Qualify fit-for-purpose models for their specific context of use

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Read the publication - Open Access ↗︎