Nonnucleoside reverse transcriptase inhibitor pharmacokinetics in a large unselected cohort of HIV-infected women.
Nonnucleoside reverse transcriptase inhibitor pharmacokinetics in a large unselected cohort of HIV-infected women.
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DOI：
10.1097/qai.0b013e31819c3376
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发表时间：
2009-04-15
期刊：
影响因子：
--
通讯作者：
Women's Interagency HIV Study
中科院分区：
文献类型：
--
作者：
Gandhi M;Benet LZ;Bacchetti P;Kalinowski A;Anastos K;Wolfe AR;Young M;Cohen M;Minkoff H;Gange SJ;Greenblatt RM;Women's Interagency HIV Study
早期试验中药物的小型强化药代动力学 (PK) 研究无法确定影响异质人群药物暴露的因素范围。我们在实际使用条件下对大量 HIV 感染女性进行了非核苷类逆转录酶抑制剂 (NNRTI) 的 PK 研究，以评估影响暴露的患者特征，并评估暴露与反应之间的关系。女性机构间 HIV 研究 (WIHS) 的 225 名接受基于 NNRTI 抗逆转录病毒治疗方案的女性被纳入 12 或 24 小时 PK 研究。在访问之前和访问期间收集了大量的人口统计、实验室和药物协变量数据，用于多变量模型。总 NNRTI 药物暴露量通过浓度-时间曲线下面积 (AUC) 估算。在多变量分析中，肝脏炎症和肾功能不全与奈韦拉平（NVP）暴露增加独立相关；强效可卡因、高脂肪饮食和闭经与水平下降有关 (n=106)。随着转氨酶、白蛋白水平和橙汁消耗量的增加，依非韦伦 (EFV) 暴露量也会增加；替诺福韦的使用、体重增加、非裔美国人和闭经与暴露量减少有关 (n=119)。 NVP 或 EFV 暴露量每增加 10 倍，参与者出现病毒学抑制的可能性分别增加 3.3 倍和 3.6 倍。药物暴露量较高的患者也更有可能报告治疗副作用。我们的研究确定并量化了以前未被识别的影响“现实世界”环境中 NNRTI 暴露的因素。在代表性人群中进行全面的 PK 研究是可行的，并且最终可能会导致针对有失败或不良事件风险的患者采取剂量优化策略。
Small intensive pharmacokinetic (PK) studies of medications in early-phase trials cannot identify the range of factors that influence drug exposure in heterogeneous populations. We performed PK studies in large numbers of HIV-infected women on nonnucleoside-reverse-transcriptase-inhibitors (NNRTIs) under conditions of actual use to assess patient characteristics that influence exposure and evaluated the relationship between exposure and response. 225 women on NNRTI-based antiretroviral regimens from the Women’s Interagency HIV Study (WIHS) were enrolled into 12 or 24-hour PK studies. Extensive demographic, laboratory and medication covariate data was collected before and during the visit to be used in multivariate models. Total NNRTI drug exposure was estimated by area-under-the-concentration-time curves (AUC). Hepatic inflammation and renal insufficiency were independently associated with increased nevirapine (NVP) exposure in multivariate analyses; crack cocaine, high fat diets, and amenorrhea were associated with decreased levels (n=106). Higher efavirenz (EFV) exposure was seen with increased transaminase, albumin levels, and orange juice consumption; tenofovir use, increased weight, being African-American and amenorrhea were associated with decreased exposure (n=119). With every 10-fold increase in NVP or EFV exposure, participants were 3.3 and 3.6 times as likely to exhibit virologic suppression, respectively. Patients with higher drug exposure were also more likely to report side effects on therapy. Our study identifies and quantitates previously unrecognized factors modifying NNRTI exposure in the “real-world” setting. Comprehensive PK studies in representative populations are feasible and may ultimatley lead to dose optimization strategies in patients at risk for failure or adverse events.
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