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Physiologically-based pharmacokinetic model to investigate the effect of pregnancy on risperidone and paliperidone pharmacokinetics: Application to a pregnant woman and her neonate

Mahdy, Walaa Y. B. Yamamoto, Kazuhiro Ito, Takahiro Fujiwara, Naoko Fujioka, Kazumichi Horai, Tadasu Otsuka, Ikuo Imafuku, Hitomi Omura, Tomohiro Iijima, Kazumoto Yano, Ikuko 神戸大学

2023.04

概要

This study aimed to determine the effects of pregnancy and ontogeny on risperidone and paliperidone pharmacokinetics by assessing their serum concentrations in two subjects and constructing a customized physiologically-based pharmacokinetic (PBPK) model. Risperidone and paliperidone serum concentrations were determined in a pregnant woman and her newborn. PBPK models for risperidone and paliperidone in adults, pediatric, and pregnant populations were developed and verified using the Simcyp simulator. These models were then applied to our two subjects, generating their “virtual twins.” Effects of pregnancy on both drugs were examined using models with fixed pharmacokinetic parameters. In the neonatal PBPK simulation, 10 different models for estimating the renal function of neonates were evaluated. Risperidone was not detected in the serum of both pregnant woman and her newborn. Maternal and neonatal serum paliperidone concentrations were between 2.05–3.80 and 0.82–1.03 ng/ml, respectively. Developed PBPK models accurately predicted paliperidone's pharmacokinetics, as shown by minimal bias and acceptable precision across populations. The individualized maternal model predicted all observed paliperidone concentrations within the 90% prediction interval. Fixed-parameter simulations showed that CYP2D6 activity largely affects risperidone and paliperidone pharmacokinetics during pregnancy. The Flanders metadata equation showed the lowest absolute bias (mean error: 22.3% ± 6.0%) and the greatest precision (root mean square error: 23.8%) in predicting paliperidone plasma concentration in the neonatal population. Our constructed PBPK model can predict risperidone and paliperidone pharmacokinetics in pregnant and neonatal populations, which could help with precision dosing using the PBPK model-informed approach in special populations.

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SUPPORTING INFORMATION

Additional supporting information can be found online

in the Supporting Information section at the end of this

article.

How to cite this article: Mahdy WYB, Yamamoto

K, Ito T, et al. Physiologically-based

pharmacokinetic model to investigate the effect of

pregnancy on risperidone and paliperidone

pharmacokinetics: Application to a pregnant

woman and her neonate. Clin Transl Sci. 2023;16:

618-630. doi:10.1111/cts.13473

17528062, 2023, 4, Downloaded from https://ascpt.onlinelibrary.wiley.com/doi/10.1111/cts.13473 by Kobe University, Wiley Online Library on [19/04/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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