University of California, San Francisco, 94143-0622, USA.
AIDS. 2012 Apr 24;26(7):833-41. doi: 10.1097/QAD.0b013e328351a521.
To estimate nevirapine (NVP) pharmacokinetics and examine its association with rash and/or hepatotoxicity in women starting antiretroviral treatment in the AIDS Clinical Trials Group A5208/OCTANE study in Africa.
In HIV-infected, nonpregnant women with screening CD4 cell count less than 200 cells/μl randomized to NVP (twice daily, after 14-day once-daily lead-in period) and tenofovir/emtricitabine, single NVP blood samples were collected 14 and 28 days following randomization. Rash and hepatotoxicity that occurred during therapy, or within 7 days after the last dose of NVP, were defined as toxicity.
NVP pharmacokinetics were modeled by population pharmacokinetic analysis. Individual Bayesian pharmacokinetic estimates were used to calculate clearance, 24-h area under the curve, and predicted plasma concentrations.
Median week 4 NVP clearance was 2 l/h. Among the 359 women, 194 (54%) developed a rash of any grade; 82 (23%) had grade 2+ and nine (3%) had grade 3+ rash. Median clearance was 1.7 l/h for participants exhibiting 3+ rash versus 2 l/h in women without 3+ rash (P = 0.046). The odds of developing 3+ rash was 50% higher for every 20% decrease in clearance (P = 0.046). NVP discontinuation due to rash/liver toxicity was significantly more common among women with pretreatment CD4 cell count more than 250 cells/μl (P = 0.003).
In this study, HIV-infected African women starting a NVP-based antiretroviral regimen had a lower NVP clearance compared to previous reports. Severe rash, but not hepatotoxicity, was associated with higher NVP exposure. Albeit observed in a small number of women, baseline CD4 cell count at least 250 cells/μl was significantly associated with NVP toxicity.
估算奈韦拉平（NVP）的药代动力学，并在非洲艾滋病临床试验组 A5208/OCTANE 研究中，评估其与开始接受抗逆转录病毒治疗的女性中皮疹和/或肝毒性的关系。
在筛选 CD4 细胞计数低于 200 个/μl 的 HIV 感染非妊娠妇女中，随机分为 NVP（每日两次，在 14 天的每日一次导入期后）和替诺福韦/恩曲他滨，在随机分组后 14 和 28 天采集单次 NVP 血样。在治疗期间或最后一剂 NVP 后 7 天内发生的皮疹和肝毒性定义为毒性。
通过群体药代动力学分析对 NVP 药代动力学进行建模。使用个体贝叶斯药代动力学估算值来计算清除率、24 小时 AUC 和预测的血浆浓度。
中位第 4 周 NVP 清除率为 2 l/h。在 359 名女性中，194 名（54%）出现任何级别皮疹；82 名（23%）出现 2+级皮疹，9 名（3%）出现 3+级皮疹。出现 3+级皮疹的参与者中位清除率为 1.7 l/h，而无 3+级皮疹的女性中位清除率为 2 l/h（P = 0.046）。清除率每降低 20%，出现 3+级皮疹的可能性增加 50%（P = 0.046）。由于皮疹/肝毒性而停药的情况在预处理 CD4 细胞计数超过 250 个/μl 的女性中更为常见（P = 0.003）。
在这项研究中，开始接受 NVP 为基础的抗逆转录病毒治疗的非洲 HIV 感染女性的 NVP 清除率低于之前的报告。严重皮疹，但不是肝毒性，与更高的 NVP 暴露相关。尽管在少数女性中观察到，但基线 CD4 细胞计数至少 250 个/μl 与 NVP 毒性显著相关。
