Application of a Physiologically Based Pharmacokinetic Approach to Predict Tenofovir Pharmacokinetics During Pregnancy

Abstract

Pharmacotherapy during pregnancy requires a better understanding of the impact of changes in maternal physiology on the maternal and fetal drug exposure. The physiologically based pharmacokinetic (PBPK) modelling approach can be applied to predict maternal and fetal exposure. In vitro and in vivo PK data in non-pregnant individuals were compiled and used to develop and verify a PBPK model for tenofovir. The model was then used to predict the maternal and fetal tenofovir exposure during pregnancy, after incorporation of current knowledge on maternal and fetal physiological changes during pregnancy. Predicted concentrations and parameters from the PBPK model were compared to observed data. Predicted tenofovir PK agreed with observations in non-pregnant (13 studies) and pregnant (7 studies with differing gestational weeks) individuals. Observed concentrations fell within the PBPK 5th - 95th prediction intervals. Predicted PK parameters were within twofold of the reported parameters. The predicted tenofovir steady state cord-to-maternal exposure ratio at term was 0.85 (range: 0.62-0.98), which agrees with clinically observed ratios ranging between 0.60-1.00. A PBPK model for tenofovir was constructed and used to simulate the maternal and fetal exposure to tenofovir in virtual pregnant women population at different gestational weeks. Applying a similar approach to other drugs or chemicals may allow exposure prediction and risk assessment in the fetus following maternal administration of drugs or unintended exposure to environmental toxicants.

Keywords: PBPK; amniotic fluid; fetal; placenta; pregnancy; tenofovir.