PBPK modeling for predicting drug-drug interactions (DDI)

Inform and replace clinical DDI studies with PBPK modeling

Drug-drug interaction (DDI) studies are expensive and time-consuming. Mechanistic modeling, such as physiologically based pharmacokinetic (PBPK) modeling, is a validated approach to inform, reduce, and replace clinical DDI studies.

Written by Simcyp® PBPK experts, this white paper provides a comprehensive overview on the evolution of the regulatory landscape and highlights 13 case studies that demonstrate how PBPK modeling is being applied to predict DDIs for increasingly complex scenarios and populations.

PBPK: The gold standard for mechanistic DDI assessment

PBPK modeling is often used for DDI assessment for reasons such as:
Mechanistic integration of drug and system parameters
Extrapolation across populations and varied dosing scenarios
Integration of in vitro inhibition/induction data for enzymes and transporters
Acceptance by regulatory agencies worldwide

Regulatory agencies, including the FDA and ICH, increasingly support the use of PBPK modeling for DDI assessment through the development of guidelines, such as the ICH M12 on drug interaction studies which was finalized in May 2024.

In August 2025, the EMA formally qualified the Simcyp Simulator for predicting CYP-mediated DDIs. This is the first and only PBPK modeling platform to receive this distinction, allowing sponsors to reference a qualified PBPK platform for the defined contexts of use scenarios in EMA submissions.

“In some situations, predictive modeling approaches (mechanistic static or PBPK) can be used to translate in vitro results to the clinical setting, without a clinical DDI study.”

– ICH M12

“PBPK models can assist in the evaluation of the DDI potential of an investigational drug and/or a metabolite as an object or precipitant of enzyme or transporter-mediated interactions.”

– ICH M12

Download the white paper to discover how PBPK modeling is transforming DDI studies

What you'll learn

Understand the Role of DDIs: Delve into the critical impact DDIs have on a drug’s safety and efficacy profile and explore how PBPK modeling is driving more efficient solutions in drug development.

Comprehensive Regulatory Overview: Understand the evolution of regulatory guidelines and frameworks supporting the use of PBPK in lieu of clinical studies.

13 Real-World Case Studies: Explore examples where PBPK modeling predictions were accepted by regulatory agencies in lieu of clinical studies across increasingly complex DDI scenarios and for an increasing number of patient types.

Examples include:

DDI predictions without requiring a rifampin study
DDI predictions for long acting injectables
PBPK for time-dependent inhibition and induction
Predicting DDI for organ impaired populations
PBPK-led strategy resulting in 10+ clinical studies waived

Access the white paper

Download the white paper for free today!

About the Authors

Karen Rowland Yeo, PhD

Senior Vice President, Client & Regulatory Strategy

Karen is Senior Vice-President, Client & Regulatory Strategy at Certara UK Limited’s Simcyp Division. Prior to this, she was the Head of PBPK Consultancy Services at Simcyp where she led a team of scientists engaged in Consultancy projects relating to the application of physiologically based pharmacokinetic (PBPK) modelling in drug development. Her work has focused on the use of PBPK models for assessment of drug-drug interactions and dosing of special populations and she is the author/co-author of more than 100 peer reviewed articles in these areas.

Hannah Jones, PhD

SVP, Head of Simcyp PBPK Modeling Services

As leader of the global Simcyp PBPK services team, Hannah is passionate about using modeling approaches to make drug development more efficient and get better drugs to patients more quickly, ultimately saving patient lives. Hannah has over 20 years of experience in global organizations with a background in translational sciences. She has experience working in a range of modalities from small molecules to biologics, and cell and gene therapies across many therapeutic areas. She has over 70 publications in PBPK and PKPD modeling and other DMPK related topics. She was featured in the list of the top 2% of scientists worldwide by Elsevier BV and Stanford University from 2019-2024.

About Certara

Certara is dedicated to transforming drug discovery and development for good. We harness the power of biosimulation, advanced analytics, and regulatory expertise to create a future where treatments reach patients faster and more efficiently.

From discovery to market access and commercial, we tailor solutions to meet our clients’ most pressing challenges. Through strategic leadership and advanced predictive technologies, Certara provides comprehensive solutions to optimize drug development processes, reduce risks, and improve outcomes. Our clients include more than 2,400 biopharmaceutical companies, academic institutions, and regulatory agencies across 70 countries.