A population pharmacokinetic model was developed to explore the pharmacokinetics modification of unbound raltegravir during pregnancy. The RalFe ANRS160 study was a nonrandomized, open-label, multicenter trial enrolling HIV-infected pregnant women receiving a combined antiretroviral regimen containing 400 mg raltegravir twice daily. Biological samples were collected during the third trimester of pregnancy (between 30 and 37 weeks of gestational age) and at postpartum (4 to 6 weeks after delivery). A population pharmacokinetic model was developed with Monolix software. A total of 360 plasma samples were collected from 43 women during pregnancy and postpartum. The unbound raltegravir was described by a one-compartment model with a transit compartment with first-order absorption, evolving to bound raltegravir (by a linear binding to albumin) or metabolism to RAL-glucuronide or to a first-order elimination, with a circadian rhythm. During pregnancy, the absorption was decreased and delayed and the raltegravir elimination clearance and glucuronidation increased by 37%. Median total and unbound area under the curve from 0 to 12 h significantly decreased by 36% and 27% during pregnancy. Median total trough concentration (C_trough) decreased significantly in the evening (28%); however, the median total C_trough in the morning, unbound C_trough in the morning, and unbound C_trough in the evening showed a nonsignificant decrease of 16%, 1%, and 15%, respectively, during pregnancy compared to the postpartum period. This is the first study reporting the pharmacokinetics of unbound raltegravir during pregnancy. As unbound C_trough did not significantly decrease during the third trimester, the pregnancy effect on raltegravir unbound concentrations was not considered clinically relevant. (This study has been registered at ClinicalTrials.gov under identifier NCT02099474.)

中文翻译：

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妊娠对ANRS 160 RalFe试验中未结合的Raltegravir浓度的影响。

开发了群体药代动力学模型以探索未结合的raltegravir在怀孕期间的药代动力学修饰。RalFe ANRS160研究是一项非随机，开放标签，多中心试验，招募了接受HIV感染的孕妇，该孕妇每天两次接受包含400 mg raltegravir的联合抗逆转录病毒疗法。在妊娠晚期（胎龄30至37周之间）和产后（分娩后4至6周）收集生物样品。使用Monolix软件开发了群体药代动力学模型。在怀孕和产后共从43名妇女中收集了360份血浆样品。用具有一阶吸收的转运室的单室模型描述了未结合的raltegravir，逐渐发展为结合的拉格达韦（通过与白蛋白线性结合）或代谢为RAL-葡糖醛酸或一级消除，并伴有昼夜节律。在怀孕期间，吸收减少并延迟，raltegravir消除清除率和葡萄糖醛酸苷化增加37％。在怀孕期间，从0到12 h曲线下的中值总和未绑定区域分别显着减少了36％和27％。总谷浓度中位数（C_槽）在晚上显着下降（28％）；然而，与产后相比，怀孕期间早晨的总C_谷，早晨的未约束C_谷和晚上的未约束C_谷的中值分别显示了16％，1％和15％的显着下降。这是第一项报道未结合的raltegravir在怀孕期间的药代动力学的研究。由于未结合的C_谷在妊娠中期没有显着降低，因此对拉格列韦未结合浓度的妊娠影响在临床上不被认为是相关的。（该研究已在ClinicalTrials.gov上注册，标识为NCT02099474。）