Regulatory Considerations for the Mother, Fetus and Neonate in Fetal Pharmacology Modeling

Abstract

The regulatory framework for considering the fetal effects of new drugs is limited. This is partially due to the fact that pediatric regulations (21 CFR subpart D) do not apply to the fetus, and only US Health and Human Service (HHS) regulations apply to the fetus. The HHS regulation 45 CFR Part 46 Subpart B limits research approvable by an institutional review board to research where the risk to the fetus is minimal unless the research holds out the prospect of a direct benefit to the fetus or the pregnant woman (45 CFR 46.204). Research that does not meet these requirements, but presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health of pregnant women, fetuses, or neonates, may be permitted by the Secretary of the HHS after expert panel consultation and opportunity for public review and comment (45 CFR 46.407). If the product is regulated by the US Food and Drug Administration (FDA), FDA may get involved in the review process. The FDA does however have a Reviewer Guidance on Evaluating the Risks of Drug Exposure in Human Pregnancies from 2005 and this guidance does discuss the intensity of drug exposure. Estimation of that exposure using physiologically based pharmacokinetic (PBPK) modeling has been suggested by some investigators. Given that drug exposure during pregnancy will impact the fetus, a number of new guidances in the last 2 years also address inclusion of pregnant women in clinical drug trials. Therefore, the drug-specific information on fetal pharmacology will increase dramatically in the next decade due to interest in drugs administered in pregnancy and with the assistance of model-informed drug development.

Mechanistic Modeling of Placental Drug Transfer in Humans: How Do Differences in Maternal/Fetal Fraction of Unbound Drug and Placental Influx/Efflux Transfer Rates Affect Fetal Pharmacokinetics?

“…While pregnant women have historically been excluded from clinical trials, the lack of drug studies in pregnant women has been recognized as a major health issue (76). There seems to be a slow paradigm shift arguing in favor of the inclusion of pregnant women in clinical research (77)(78)(79) which is also, at least to some extent, reflected by recent guidance documents from the US Food and Drug Administration (FDA) (7). Hence, it can be expected that more clinical data in pregnant women will be generated within the next years.…”

“…Of note, f water _ pls , f water _ int and the ratio were assumed to be the same as in the adult organism, namely 0.926 ( 22 ), 0.935 ( 22 ), and 0.37 ( 23 ), respectively. Inserting Equation ( 6 ) into Equation ( 3 ) yields Equation ( 7 ) which was used in the updated maternal-fetal PBPK model.…”

“…As clinical studies involving pregnant women are difficult to conduct due to various considerations ( 5 ), other approaches are needed as alternative or complementary tools to elucidate maternal-fetal pharmacology. Among these tools, physiologically based pharmacokinetic (PBPK) modeling holds potential to improve the conceptual and quantitative understanding of maternal-fetal pharmacokinetics ( 6 , 7 ). PBPK models integrate compound-specific properties (e.g., lipophilicity, molecular weight) and physiological and biological characteristics (e.g., organ volumes and blood flow rates) in a mechanistic framework ( 8 ).…”

Maternal–Fetal Drug Development: An Industry Perspective

“…However, regulations to study medicines in pregnant women and their fetuses remain limited. 4 The United States Congress passed the Best Pharmaceuticals for Children Act (BPCA) in 2002 and the Pediatric Research Equity Act (PREA) in 2003 to help promote the study of medicines in children. 5,6 The BPCA is a voluntary program to incentivize the completion of pediatric clinical trials by providing additional marketing exclusivity to drug developers.…”

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.…”