Ideal Time to Conduct a Pharmacokinetic Investigation After Delivery to Fully Capture the Effect of Pregnancy on Drug Exposure.

BACKGROUND

The World Health Organization is pushing to accelerate the study of new human immunodeficiency virus drugs in pregnant women. However, regulatory guidelines do not specify when to conduct pharmacokinetic studies in postpartum women. This knowledge gap carries the potential to jeopardize the outcomes and conclusions of clinical trials aiming to study the effect of pregnancy on drug exposure. We used physiologically based pharmacokinetic (PBPK) modeling along with clinical data to determine the time needed after delivery for drug exposure to return to prepregnancy levels.

METHODS

A literature review was conducted to collect physiological parameters of pregnant and postpartum women. Regression analyses were performed to derive equations describing the parameters trajectory throughout pregnancy and post partum to inform our PBPK model. Published pharmacokinetic data in pregnant and postpartum women were used for the model verification. The PBPK model was subsequently applied to investigate pharmacokinetic changes throughout pregnancy and post partum.

RESULTS

In agreement with the clinical data the PBPK model was able to describe the different effects of pregnancy on drug exposure, with bictegravir showing the largest reduction in exposure (approximately 50%) during the third trimester while ritonavir and raltegravir showing the lowest (approximately 30%). The successfully verified PBPK model predicted that all evaluated antiretrovirals mostly return to prepregnancy exposure 4 weeks after delivery.

CONCLUSIONS

Pharmacokinetic investigations on hepatically cleared drugs should not be conducted before the fifth week after delivery to fully characterize the effect of pregnancy on drug exposure. Because physiological changes remain after delivery, early measurements can underestimate the pregnancy effect on pharmacokinetics, leading to suboptimal dosing recommendations during pregnancy.