A Physiologically-Based Pharmacokinetic Model to Predict Human Fetal Exposure for a Drug Metabolized by Several CYP450 Pathways
A Physiologically-Based Pharmacokinetic Model to Predict Human Fetal Exposure for a Drug Metabolized by Several CYP450 Pathways
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DOI：
10.1007/s40262-016-0457-5
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发表时间：
2017-05-01
影响因子：
4.5
通讯作者：
Benaboud, Sihem
中科院分区：
文献类型：
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作者：
Mendes, Mailys De Sousa;Lui, Gabrielle;Benaboud, Sihem
背景孕妇及其胎儿暴露于多种药物中，然而，就药物的安全性和有效性而言，她们是孤儿群体。方法通过细胞色素P450(CYP)3A4、2B6和2D6途径代谢奈韦拉平的生理学药代动力学(PBPK)模型，预测母婴药物动力学。该模型是在非怀孕和怀孕妇女中建立的，并考虑了所有可能影响奈韦拉平PK的生理和酶变化。在这个PBPK模型中包含了从体外人胎盘灌流实验中估计的经胎盘参数。为了验证模型的有效性，将孕妇和脐带血的观察浓度与预测浓度进行了比较，并研究了胎儿排泄对胎儿PK的影响。结果通过实施包括CYP3A4、2D6和2B6诱导在内的生理变化，我们预测在妊娠晚期清除量将增加21%。PBPK模型成功地预测了非怀孕和怀孕人群的倾向。从体外实验中获得的参数可以预测奈韦拉平的浓度，与观察到的脐带血浓度相匹配。曲线下的母胎面积(0~2 4h间隔)为0.77，胎儿代谢对胎儿PK值无显著影响。结论PBPK法是一种有效的方法，可用于预测孕期代谢性药物的先验暴露，可用于评价不同给药方案以优化药物治疗。这种方法，包括体外人体胎盘血流灌注参数，是预测人类胎儿暴露的一种有前途的方法。
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.