Leveraging the draft FDA Guidance on PBPK for your drug development program

24 February 2021

Clinical Pharmacology, Modeling and Simulation (CPMS), Parexel International

In October of 2020, the Food and Drug Administration (FDA) issued draft guidance for the pharmaceutical industry on The Use of Physiologically Based Pharmacokinetic Analyses — Biopharmaceutics Applications for Oral Drug Product Development, Manufacturing Changes, and Controls; you can find a copy of the draft guidance here - https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-physiologically-based-pharmacokinetic-analyses-biopharmaceutics-applications-oral-drug-product

Physiologically based pharmacokinetic (PBPK) analysis combines physiological descriptions (blood flow, tissue volume, partition coefficients, etc) and population estimates, along with the unique drug substance and drug product characteristics to model and simulate the pharmacokinetic and/or pharmacodynamic behaviors in vivo. The draft guidance offers several high-level workflows that include defining the objective of a PBPK model, model development including structure, assumptions and parameterization, model validation, and the critical step of application of the model to purpose. The guidance is only applicable for biopharmaceutics applications of orally administered drugs.

“We know that the industry standard will quickly embrace these concepts and every new orally administered drug approval will contain a rigorously developed and validated PBPK model,” notes Anita Nelson, Sr. VP of Translational Medicine that oversees CPMS at Parexel. “A review of all NDA/BLA submissions to OCP as of late 2019 showed that 50% of the new drug approvals contained PBPK modeling and analyses.¹

A large portion of the guidance focuses on the concept of supporting product quality and Quality by Design using PBPK modeling. The strong predictive capabilities of properly developed and validated PBPK models make them ideal for use in formulation development, dissolution method development, derivation of product specifications, and product life-cycle management. Sponsors are advised to incorporate dissolution profiles into the PBPK model development, utilize the model to predict in vivo exposures and determine if the predictions are within 10% of the actual data.

This type of guidance is critical to groups such as Parexel’s Clinical Pharmacology, Modeling and Simulation division to offer our clients approaches that are in-line with Agency expectations as the utility of modeling and simulation moves from a bonus step to an expected one. We will need to critically review this and other guidance on the topic of PBPK modeling applications, determine where there are gaps in the approach, and, as industry-leaders, propose advancements and modifications for this ever-evolving field.

Parexel’s Clinical Pharmacology, Modeling and Simulation team encompasses approximately 33 scientists and analysts from around the globe. Our expert pharmacometricians are well poised to assist companies in the development, validation, and application of physiologically based pharmacokinetic modeling. For further information, contact Joseph Kim, PhD, RPh, VP, Clinical Pharmacology, Modeling and Simulation.

1. PBPK Current Status and Challenges: A Regulatory Perspective Yaning Wang, Ph.D. Division of Pharmacometrics Office of Clinical Pharmacology OTS/CDER/OMTP/FDA. Development of Best Practices in Physiologically Based Pharmacokinetic Modeling to Support Clinical Pharmacology Regulatory Decision-Making.

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