Physiologically Based Pharmacokinetic Modeling in Pregnant Women Suggests Minor Decrease in Maternal Exposure to Olanzapine

Abstract

Pregnancy is accompanied by significant physiological changes that might affect the in vivo drug disposition. Olanzapine is prescribed to pregnant women with schizophrenia, while its pharmacokinetics during pregnancy remains unclear. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of olanzapine in the pregnant population. With the contributions of each clearance pathway determined beforehand, a full PBPK model was developed and validated in the non-pregnant population. This model was then extrapolated to predict steady-state pharmacokinetics in the three trimesters of pregnancy by introducing gestation-related alterations. The model adequately simulated the reported time-concentration curves. The geometric mean fold error of Cmax and AUC was 1.14 and 1.09, respectively. The model predicted that under 10 mg daily dose, the systematic exposure of olanzapine had minor changes (less than 28%) throughout pregnancy. We proposed that the reduction in cytochrome P4501A2 activity is counteracted by the induction of other enzymes, especially glucuronyltransferase1A4. In conclusion, the PBPK model simulations suggest that, at least at the tested stages of pregnancy, dose adjustment of olanzapine can hardly be recommended for pregnant women if effective treatment was achieved before the onset of pregnancy and if fetal toxicity can be ruled out.