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