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

Author:

Werdan Romão Marya Antônya1,Pinto Leonardo2,Cavalli Ricardo Carvalho3,Duarte Geraldo3,de Moraes Natália Valadares4ORCID,Abduljalil Khaled5ORCID,Moreira Fernanda de Lima1ORCID

Affiliation:

1. Laboratório de Farmacometria (LabFarma) Faculdade de Farmácia Universidade Federal do Rio de Janeiro Rio de Janeiro RJ Brazil

2. Universidade Federal de Ouro Preto Ouro Preto MG Brazil

3. Departamento de Obstetrícia e Ginecologia Faculdade de Medicina de Ribeirão Preto Universidade de São Paulo Ribeirão Preto SP Brazil

4. Center for Pharmacometrics and Systems Pharmacology Department of Pharmaceutics College of Pharmacy University of Florida Orlando FL USA

5. Simcyp Division Certara UK Limited Sheffield UK

Abstract

AbstractNifedipine 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.

Funder

Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro

Publisher

Wiley

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