Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
Clin Pharmacokinet. 2018 Jun;57(6):705-716. doi: 10.1007/s40262-017-0583-8.
Fetal antiretroviral exposure is usually derived from the cord-to-maternal concentration ratio. This static parameter does not provide information on the pharmacokinetics in utero, limiting the assessment of a fetal exposure-effect relationship.
The aim of this study was to incorporate placental transfer into a pregnancy physiologically based pharmacokinetic model to simulate and evaluate fetal darunavir exposure at term.
An existing and validated pregnancy physiologically based pharmacokinetic model of maternal darunavir/ritonavir exposure was extended with a feto-placental unit. To parameterize the model, we determined maternal-to-fetal and fetal-to-maternal darunavir/ritonavir placental clearance with an ex-vivo human cotyledon perfusion model. Simulated maternal and fetal pharmacokinetic profiles were compared with observed clinical data to qualify the model for simulation. Next, population fetal pharmacokinetic profiles were simulated for different maternal darunavir/ritonavir dosing regimens.
An average (±standard deviation) maternal-to-fetal cotyledon clearance of 0.91 ± 0.11 mL/min and fetal-to-maternal clearance of 1.6 ± 0.3 mL/min was determined (n = 6 perfusions). Scaled placental transfer was integrated into the pregnancy physiologically based pharmacokinetic model. For darunavir 600/100 mg twice a day, the predicted fetal maximum plasma concentration, trough concentration, time to maximum plasma concentration, and half-life were 1.1, 0.57 mg/L, 3, and 21 h, respectively. This indicates that the fetal population trough concentration is higher or around the half-maximal effective darunavir concentration for a resistant virus (0.55 mg/L).
The results indicate that the population fetal exposure after oral maternal darunavir dosing is therapeutic and this may provide benefits to the prevention of mother-to-child transmission of human immunodeficiency virus. Moreover, this integrated approach provides a tool to prevent fetal toxicity or enhance the development of more selectively targeted fetal drug treatments.
胎儿抗逆转录病毒暴露通常来自脐带与母体浓度比。这个静态参数不能提供胎儿体内药代动力学的信息，限制了对胎儿暴露-效应关系的评估。
本研究旨在将胎盘转运纳入妊娠生理药代动力学模型，以模拟和评估足月胎儿达芦那韦的暴露情况。
我们扩展了现有的、经验证的母体达芦那韦/利托那韦暴露妊娠生理药代动力学模型，并增加了一个胎-胎盘单位。为了对模型进行参数化，我们用离体人绒毛膜胎盘灌注模型确定了母体-胎儿和胎儿-母体达芦那韦/利托那韦胎盘清除率。将模拟的母体和胎儿药代动力学曲线与观察到的临床数据进行比较，以验证模型的适用性。然后，模拟了不同母体达芦那韦/利托那韦给药方案的人群胎儿药代动力学曲线。
平均（±标准偏差）母体-胎盘绒毛清除率为 0.91±0.11 mL/min，胎儿-母体清除率为 1.6±0.3 mL/min（n=6 次灌注）。缩放后的胎盘转运被整合到妊娠生理药代动力学模型中。对于达芦那韦 600/100 mg 每日两次，预测的胎儿最大血浆浓度、谷浓度、达到最大血浆浓度的时间和半衰期分别为 1.1、0.57 mg/L、3 和 21 h。这表明胎儿人群的谷浓度高于或接近耐药病毒的达芦那韦半最大有效浓度（0.55 mg/L）。
结果表明，口服母体达芦那韦给药后的人群胎儿暴露是治疗性的，这可能有助于预防艾滋病毒母婴传播。此外，这种综合方法提供了一种工具，可以预防胎儿毒性或增强更有针对性的胎儿药物治疗的发展。
