Interaction between Artemether-Lumefantrine and Nevirapine-Based Antiretroviral Therapy in HIV-1-Infected Patients
Interaction between Artemether-Lumefantrine and Nevirapine-Based Antiretroviral Therapy in HIV-1-Infected Patients
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DOI：
10.1128/aac.05265-11
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发表时间：
2011-12-01
影响因子：
4.9
通讯作者：
Barnes, K. I.
中科院分区：
文献类型：
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作者：
Kredo, T.;Mauff, K.;Barnes, K. I.
在非洲，以蒿甲醚-氨苯曲明和奈韦拉平为基础的抗逆转录病毒疗法（ART）分别是疟疾和艾滋病毒最常推荐的一线治疗方法。甲醚、氨芳碱和奈韦拉平通过细胞色素P450 3A4酶系统代谢，奈韦拉平诱导细胞色素P450 3A4酶系统代谢，从而产生重要的药物相互作用。在一项平行设计的药代动力学研究中，获得了两组hiv感染患者的浓度-时间曲线：art初始患者和那些在奈韦拉平基础治疗下稳定的患者。两组均给予推荐剂量的蒿甲醚-氨芳碱。患者入院接受密集药代动力学采样（0至72小时），门诊采样至21天。采用高效液相色谱-串联质谱法（LC-MS/MS）测定样品中氨芳碱、蒿甲醚、双氢青蒿素和奈韦拉平的浓度。主要结果是观察第7天的氨芳碱浓度，因为这些浓度与疟疾的治疗反应有关。我们招募了36名患者（32名女性）。在奈韦拉平组和art初始组中，第7天的中位（范围）氨芳碱浓度分别为622 ng/ml （185 ~ 2040 ng/ml）和336 ng/ml (29 ~ 934 ng/ml) （P = 0.0002）。奈韦拉平组在0 ~ 8 h血浆浓度-时间曲线下的青蒿素中位面积[AUC((0 ~ 8 h))] （P < 0.0001）和双氢青蒿素AUC((60 ~ 68 h)) （P = 0.01）均较低。仅奈韦拉平组蒿甲醚和双氢青蒿素联合暴露随时间减少（几何平均比[GMR]， 0.76[95%可信区间{CI}， 0.65至0.90],P < 0.0001），并随体重调整后蒿甲醚剂量增加（GMR, 2.12 [95% CI， 1.31至3.45],P = 0.002）。不良事件组间相似，心电图Fridericia校正QT间期和预期最大氟苯曲明浓度（T(max)）时的P-R间期无差异。以奈韦拉平为基础的抗逆转录病毒治疗降低了蒿甲醚和双氢青蒿素auc，但意外地增加了氨芳碱暴露。其相互作用机制尚待阐明。迫切需要研究奈韦拉平和蒿甲醚-氨苯曲明在艾滋病毒感染的疟疾患者中的相互作用。
Artemether-lumefantrine and nevirapine-based antiretroviral therapy (ART) are the most commonly recommended first-line treatments for malaria and HIV, respectively, in Africa. Artemether, lumefantrine, and nevirapine are metabolized by the cytochrome P450 3A4 enzyme system, which nevirapine induces, creating potential for important drug interactions. In a parallel-design pharmacokinetic study, concentration-time profiles were obtained in two groups of HIV-infected patients: ART-naive patients and those stable on nevirapine-based therapy. Both groups received the recommended artemether-lumefantrine dose. Patients were admitted for intense pharmacokinetic sampling (0 to 72 h) with outpatient sampling until 21 days. Concentrations of lumefantrine, artemether, dihydroartemisinin, and nevirapine were determined by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The primary outcome was observed day 7 lumefantrine concentrations, as these are associated with therapeutic response in malaria. We enrolled 36 patients (32 females). Median (range) day 7 lumefantrine concentrations were 622 ng/ml (185 to 2,040 ng/ml) and 336 ng/ml (29 to 934 ng/ml) in the nevirapine and ART-naive groups, respectively (P = 0.0002). The median artemether area under the plasma concentration-time curve from 0 to 8 h [AUC((0-8 h))] (P < 0.0001) and dihydroartemisinin AUC((60-68 h)) (P = 0.01) were lower in the nevirapine group. Combined artemether and dihydroartemisinin exposure decreased over time only in the nevirapine group (geometric mean ratio [GMR], 0.76 [95% confidence interval {CI}, 0.65 to 0.90]; P < 0.0001) and increased with the weight-adjusted artemether dose (GMR, 2.12 [95% CI, 1.31 to 3.45]; P = 0.002). Adverse events were similar between groups, with no difference in electrocardiographic Fridericia corrected QT and P-R intervals at the expected time of maximum lumefantrine concentration (T(max)). Nevirapine-based ART decreased artemether and dihydroartemisinin AUCs but unexpectedly increased lumefantrine exposure. The mechanism of the lumefantrine interaction remains to be elucidated. Studies investigating the interaction of nevirapine and artemether-lumefantrine in HIV-infected patients with malaria are urgently needed.