Physiologically Based Pharmacokinetics Model in Pregnancy: A Regulatory Perspective on Model Evaluation

Abstract

Physiologically based pharmacokinetics (PBPK) modelling is widely used in medicine development and regulatory submissions. The lack of clinical pharmacokinetic data in pregnancy is widely acknowledged; therefore, one area of current interest is in the use of PBPK modelling to describe the potential impact of anatomical and physiological changes during pregnancy on the medicine's pharmacokinetics. PBPK modelling could possibly represent a predictive tool to support the medicine benefit–risk decision and inform dose adjustment in this population and also to investigate medicine levels in the foetus to support the risk assessment to the foetus. In the context of regulatory application, there are, however, a number of considerations around model evaluation, and this should be tailored to the model purpose, in order to inform the confidence in the model for the intended application. A number of gestational age-related physiological changes are expected to alter the pharmacokinetics of medicines during pregnancy, and there are uncertainties on some parameters; therefore, well-qualified models are needed to improve assurance in the model prediction before this approach can be used to inform with confidence high-impact decisions as part of regulatory submissions.

Mathematical modeling of regulatory networks of intracellular processes – Aims and selected methods

“…There are many examples of PBPK models fine-tuned for special requirements (e.g., drugs administered by inhalation) [36] . PBPK models found their use in analysis of drug pharmacokinetics [142] , pharmacogenomics [46] , species extrapolation [54] , and special populations (children [8] , women during pregnancy [25] , diabetes [72] ). Number of submissions containing PBPK studies to regulatory authorities (FDA, EMA and PMDA, Japan) is rapidly increasing over last decades [34] .…”

Addressing drug safety of maternal therapy during breastfeeding using physiologically‐based pharmacokinetic modeling

“…Thereafter, the infant daily dose and RIDD of a drug based on ingestion via breast milk can be predicted from the simulated milk concentration profiles and used to guide neonatal/infant risk assessment where clinical lactation data are lacking. In the context of regulatory application, “well‐qualified models” are required to provide assurances that the model predictions are robust and this approach can be used to inform with confidence, high‐impact decisions as part of regulatory submissions 6 . Although it is accepted that this is an emerging and significant area of interest, evaluation of such approaches is already ongoing and results are promising 1,4 …”

“…In the context of regulatory application, “well‐qualified models” are required to provide assurances that the model predictions are robust and this approach can be used to inform with confidence, high‐impact decisions as part of regulatory submissions. 6 Although it is accepted that this is an emerging and significant area of interest, evaluation of such approaches is already ongoing and results are promising. 1 , 4 …”

Physiologically Based Pharmacokinetic Modeling in Pregnant Women Suggests Minor Decrease in Maternal Exposure to Olanzapine

“…Physiologically based pharmacokinetic (PBPK) modeling serves as a critical pharmacometrics tool to make reliable pharmacokinetic predictions in special populations. The number of new drug application submissions to the US Food and Drug Administration (FDA) that included PBPK modeling for pediatric drug development has continued to grow over the past decade ( Corriol-Rohou and Cheung, 2019 ) and the role of PBPK modeling for pregnant women in a regulatory context has been discussed recently ( Coppola et al, 2021 ; Green et al, 2021 ). Since PBPK is a mechanism-based modeling method, the combined effects of multiple gestation-related physiological changes on drug disposition can be incorporated.…”