Mechanistic Framework to Predict Maternal-Placental-Fetal Pharmacokinetics of Nifedipine Employing Physiologically Based Pharmacokinetic Modeling Approach.

Publisher: Wiley Country of Publication: England NLM ID: 0366372 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-4604 (Electronic) Linking ISSN: 00912700 NLM ISO Abbreviation: J Clin Pharmacol Subsets: MEDLINE

Publication: 2013- : Oxford : Wiley
Original Publication: Stamford, Conn., Hall Associates.

Nifedipine*/pharmacokinetics ; Nifedipine*/administration & dosage ; Maternal-Fetal Exchange* ; Models, Biological* ; Placenta*/metabolism; Humans ; Pregnancy ; Female ; Caco-2 Cells ; Fetus/metabolism ; Adult ; Cytochrome P-450 CYP3A/metabolism

Nifedipine is used for treating mild to severe hypertension and preventing preterm labor in pregnant women. Nevertheless, concerns about nifedipine fetal exposure and safety are always raised. The aim of this study was to develop and validate a maternal-placental-fetal nifedipine physiologically based pharmacokinetic (PBPK) model and apply the model to predict maternal, placental, and fetal exposure to nifedipine at different pregnancy stages. A nifedipine PBPK model was verified with nonpregnant data and extended to the pregnant population after the inclusion of the fetoplacental multicompartment model that accounts for the placental tissue and different fetal organs within the Simcyp Simulator version 22. Model parametrization involved scaling nifedipine transplacental clearance based on Caco-2 permeability, and fetal hepatic clearance was obtained from in vitro to in vivo extrapolation encompassing cytochrome P450 3A7 and 3A4 activities. Predicted concentration profiles were compared with in vivo observations and the transplacental transfer results were evaluated using 2-fold criteria. The PBPK model predicted a mean cord-to-maternal plasma ratio of 0.98 (range, 0.86-1.06) at term, which agrees with experimental observations of 0.78 (range, 0.59-0.93). Predicted nifedipine exposure was 1.4-, 2.0-, and 3.0-fold lower at 15, 27, and 39 weeks of gestation when compared with nonpregnant exposure, respectively. This innovative PBPK model can be applied to support maternal and fetal safety assessment for nifedipine at various stages of pregnancy.
(© 2024, The American College of Clinical Pharmacology.)

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E-26/204.526/2022 Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro

Keywords: PBPK; fetus; nifedipine; placenta; pregnancy

I9ZF7L6G2L (Nifedipine)
EC 1.14.14.1 (Cytochrome P-450 CYP3A)

Date Created: 20240202 Date Completed: 20240424 Latest Revision: 20241105

20241105

10.1002/jcph.2404

38305718