PII-101 - PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL ANALYSIS OF ANTIPSYCHOTICS BEFORE AND AFTER CHILDBIRTH.

K. Itohara¹, K. Fujita¹, Y. Kitahiro¹, N. Fujiwara¹, T. Konishi¹, M. Hashimoto¹, K. Yamamoto^1,2, T. Omura^1,3, I. Yano¹; ¹Department of Pharmacy, Kobe University Hospital, Kobe, Japan, ²Department of Integrated Clinical and Basic Pharmaceutical Science, Okayama University, Okayama, Japan, ³Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan.

Background: Pregnant women are known to undergo significant physiological changes, which in turn alter the pharmacokinetics of several drugs. We have recently reported that plasma concentrations of brexpiprazole, quetiapine, risperidone and its metabolite paliperidone were increased rapidly after delivery (Konishi et al. Ther. Drug Monit. 2024). The objective of this study was to develop physiologically-based pharmacokinetic (PBPK) models of these antipsychotics to investigate the mechanisms of pharmacokinetic changes of antipsychotics after delivery.

Methods: The PBPK models for brexpiprazole and quetiapine in healthy adults were constructed and verified using the published clinical data by the Simcyp ADME simulator version 23, and were extrapolated to the pregnancy population. The predictability of the developed pregnant PBPK models and our previously reported pregnant PBPK models of risperidone and paliperidone (Mahdy et al. Clin. Trans. Sci., 2023) was assessed using our maternal observed concentrations before delivery. Then, the simulated concentrations of four drugs using the non-pregnant parameters were compared with the maternal observed concentrations after delivery.

Results: All the verification data of area under the concentration-time curve and maximum concentration in healthy adults were within two-fold of predicted values, showing a good predictability of the constructed PBPK models. Extrapolation of each adult PBPK model to the pregnant population was confirmed, since our maternal observed concentrations were almost within the 90% prediction interval of the predicted values. The simulated time-course of plasma concentrations using parameters of non-pregnant status were well comparable with the observed plasma concentration changes of each antipsychotic after delivery.

Conclusion: PBPK model analysis supported that pharmacokinetic changes of four antipsychotics due to physiological changes as the pregnancy progresses return to the non-pregnant status immediately after delivery.