Clinical Pharmacokinetic Studies in Pregnant Women and the Relevance of Pharmacometric Tools

Background: In clinical pharmacokinetic (PK) studies, pregnant women are significantly underrepresented because of ethical and legal reasons which lead to a paucity of information on potential PK changes in this population. As a consequence, pharmacometric tools became instrumental to explore and quantify the impact of PK changes during pregnancy. Methods: We explore and discuss the typical characteristics of population PK and physiologically based pharmacokinetic (PBPK) models with a specific focus on pregnancy and postpartum. Results: Population PK models enable the analysis of dense, sparse or unbalanced data to explore covariates in order to (partly) explain inter-individual variability (including pregnancy) and to individualize dosing. For population PK models, we subsequently used an illustrative approach with ketorolac data to highlight the relevance of enantiomer specific modeling for racemic drugs during pregnancy, while data on antibiotic prophylaxis (cefazolin) during surgery illustrate the specific characteristics of the fetal compartments in the presence of timeconcentration profiles. For PBPK models, an overview on the current status of reports and papers during pregnancy is followed by a PBPK cefuroxime model to illustrate the added benefit of PBPK in evaluating dosing regimens in pregnant women. Conclusions: Pharmacometric tools became very instrumental to improve perinatal pharmacology. However, to reach their full potential, multidisciplinary collaboration and structured efforts are needed to generate more information from already available datasets, to share data and models, and to stimulate cross talk between clinicians and pharmacometricians to generate specific observations (pathophysiology during pregnancy, breastfeeding) needed to further develop the field.