Using PBPK modeling to supplement clinical data and support the safe and effective use of dolutegravir in pregnant and lactating women.

ABSTRACT: Optimal dosing in pregnant and lactating women requires an understanding of the pharmacokinetics in the mother, fetus, and breastfed infant. Physiologically-based pharmacokinetic (PBPK) modeling can be used to simulate untested scenarios and hence supplement clinical data to support dosing decisions. A PBPK model for the antiretroviral dolutegravir (mainly metabolized by UGT1A1) was verified using reported exposures in non-pregnant healthy volunteers, pregnant women, and the umbilical cord, lactating mothers, and breastfed neonates. The model was then applied to predict the impact of UGT1A1 phenotypes in extensive (EM), poor (PM), and ultra-rapid metabolizers (UM). The predicted dolutegravir maternal plasma and umbilical cord AUC in UGT1A1 PMs was 1.6-fold higher than in EMs. The predicted

SUBMITTER: Ning J 

PROVIDER: S-EPMC11578129 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature