Bridging the exposure-safety gap in the assessment of fetal exposure to maternal drugs.

INTRODUCTION: Pregnant women are customarily excluded from phase 1 and 2 clinical trials which, provide the earliest indication of drug safety and efficacy. This leads to lack of pregnancy-specific safety information for over 90% of approved drugs, including many commonly used during the first trimester.

AREAS COVERED: In this review, we highlight the importance of pregnancy-induced changes in pharmacokinetics, commonly used indices of fetal exposure to maternal drugs, and their limitations. Inter-species differences make data from animal models used in preclinical embryofetal development toxicity studies poorly translatable to humans. Real-world evidence may bridge some of this gap, but it is mostly retrospective in nature and available postmarketing. We reviewed emerging human relevant models that are showing promise in studying aspects of human pregnancy, highlighting opportunities for further advances.

EXPERT OPINION: While pregnancy exposure data may help in understanding how pregnancy might influence therapeutic outcomes, fetal drug exposure is not a metric of safety. Adequately addressing questions about drug safety during pregnancy will necessarily include a battery of assays based on human relevant models, each sufficiently validated for an aspect of Developmental and Reproductive Toxicology (DART) as its use case.