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A Physiologically-Based Pharmacokinetic Model to Predict Human Fetal Exposure for a Drug Metabolized by Several CYP450 Pathways

Abstract

Background

Pregnant women and their fetuses are exposed to numerous drugs; however, they are orphan populations with respect to the safety and efficacy of drugs. Therefore, the prediction of maternal and fetal drug exposure prior to administration would be highly useful.

Methods

A physiologically-based pharmacokinetic (PBPK) model for nevirapine, which is metabolized by the cytochrome P450 (CYP) 3A4, 2B6 and 2D6 pathways, was developed to predict maternal and fetal pharmacokinetics (PK). The model was developed in both non-pregnant and pregnant women, and all physiological and enzymatic changes that could impact nevirapine PK were taken into account. Transplacental parameters estimated from ex vivo human placenta perfusion experiments were included in this PBPK model. To validate the model, observed maternal and cord blood concentrations were compared with predicted concentrations, and the impact of fetal clearance on fetal PK was investigated.

Results

By implementing physiological changes, including CYP3A4, 2D6 and 2B6 inductions, we predicted a clearance increase of 21 % in late pregnancy. The PBPK model successfully predicted the disposition for both non-pregnant and pregnant populations. Parameters obtained from the ex vivo experiments allowed the prediction of nevirapine concentrations that matched observed cord blood concentrations. The fetal-to-maternal area under the curve ratio (0–24 h interval) was 0.77, and fetal metabolism had no significant effect on fetal PK.

Conclusions

The PBPK approach is a useful tool for quantifying a priori the drug exposure of metabolized drugs during pregnancy, and can be applied to evaluate alternative dosing regimens to optimize drug therapy. This approach, including ex vivo human placental perfusion parameters, is a promising approach for predicting human fetal exposure.

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Correspondence to Maïlys De Sousa Mendes.

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Conflict of interest

Maïlys De Sousa Mendes, Gabrielle Lui, Yi Zheng, Claire Pressiat, Deborah Hirt, Elodie Valade, Naïm Bouazza, Frantz Foissac, Stephane Blanche, Jean-Marc Treluyer, SaïkUrien and Sihem Benaboud have no conflicts of interest to declare.

Funding

This work was funded by the University of Paris V.

Additional information

S. Urien and S. Benaboud contributed equally to this work as last authors.

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De Sousa Mendes, M., Lui, G., Zheng, Y. et al. A Physiologically-Based Pharmacokinetic Model to Predict Human Fetal Exposure for a Drug Metabolized by Several CYP450 Pathways. Clin Pharmacokinet 56, 537–550 (2017). https://doi.org/10.1007/s40262-016-0457-5

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Keywords

  • Nevirapine
  • Antipyrine
  • PBPK Model
  • Free Fraction
  • Visual Predictive Check