Background and Objective

Doravirine is currently not recommended for pregnant women living with human immunodeficiency virus because efficacy and safety data are lacking. This study aimed to predict maternal and fetal doravirine exposure by integrating human placenta perfusion experiments with pregnancy physiologically based pharmacokinetic (PBPK) modeling.

Methods

Ex vivo placenta perfusions were performed in a closed–closed configuration, in both maternal-to-fetal and fetal-to-maternal directions (n = 8). To derive intrinsic placental transfer parameters from perfusion data, we developed a mechanistic placenta model. Next, we developed a maternal and fetal full-body pregnancy PBPK model for doravirine in Simcyp, which was parameterized with the derived intrinsic placental transfer parameters to predict in vivo maternal and fetal doravirine exposure at 26, 32, and 40 weeks of pregnancy. The predicted total geometric mean (GM) trough plasma concentration (C_trough) values were compared with the target (0.23 mg/L) derived from in vivo exposure–response analysis.

Results

A decrease of 55% in maternal doravirine area under the plasma concentration–time curve (AUC)_0–24h was predicted in pregnant women at 40 weeks of pregnancy compared with nonpregnant women. At 26, 32, and 40 weeks of pregnancy, predicted maternal total doravirine GM C_trough values were below the predefined efficacy target of 0.23 mg/L. Perfusion experiments showed that doravirine extensively crossed the placenta, and PBPK modeling predicted considerable fetal doravirine exposure.

Conclusion

Substantially reduced maternal doravirine exposure was predicted during pregnancy, possibly resulting in impaired efficacy. Therapeutic drug and viral load monitoring are advised for pregnant women treated with doravirine. Considerable fetal doravirine exposure was predicted, highlighting the need for clinical fetal safety data.

中文翻译：

---

通过整合基于生理的药代动力学模型和人胎盘灌注实验预测母胎多拉韦林暴露

背景与目的

由于缺乏有效性和安全性数据，目前不建议将多拉韦林用于感染人类免疫缺陷病毒的孕妇。本研究旨在通过将人胎盘灌注实验与妊娠生理药代动力学 (PBPK) 模型相结合来预测母体和胎儿的 doravirine 暴露。

方法

离体胎盘灌注在母体-胎儿和胎儿-母体方向上以闭合-闭合配置进行（n  = 8）。为了从灌注数据中推导出内在的胎盘转移参数，我们开发了一个机械胎盘模型。接下来，我们在 Simcyp 中开发了用于 doravirine 的母体和胎儿全身妊娠 PBPK 模型，该模型使用派生的内在胎盘转移参数进行参数化，以预测在怀孕 26、32 和 40 周时体内母体和胎儿的 doravirine 暴露。将预测的总几何平均 (GM) 谷血浆浓度 ( C_谷) 值与来自体内暴露-反应分析的目标 (0.23 mg/L) 进行比较。

结果

与非妊娠女性相比，妊娠 40 周的孕妇预计在_{0-24 小时}血浆浓度 - 时间曲线 (AUC) 下的母体多拉韦林面积减少 55% 。在妊娠 26、32 和 40 周，预测的母体总多拉韦林 GM C_谷值低于预定的疗效目标 0.23 mg/L。灌注实验表明多拉韦林广泛穿过胎盘，PBPK 模型预测胎儿大量多拉韦林暴露。

结论

预计妊娠期间母体多拉韦林暴露量显着减少，可能导致疗效受损。建议对接受多拉韦林治疗的孕妇进行治疗药物和病毒载量监测。预计胎儿会大量接触多拉韦林，这突出了对临床胎儿安全数据的需求。