Impact of Lopinavir-Ritonavir or Nevirapine on Bedaquiline Exposures and Potential Implications for Patients with Tuberculosis-HIV Coinfection
Impact of Lopinavir-Ritonavir or Nevirapine on Bedaquiline Exposures and Potential Implications for Patients with Tuberculosis-HIV Coinfection
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DOI：
10.1128/aac.03246-14
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发表时间：
2014-11-01
影响因子：
4.9
通讯作者：
Karlsson, Mats O.
中科院分区：
文献类型：
--
作者：
Svensson, Elin M.;Dooley, Kelly E.;Karlsson, Mats O.
结核病（TB）和艾滋病毒的合并治疗是推荐的，并改善结果。贝达喹啉是一种治疗耐多药结核病的新药;预期与抗逆转录病毒药物奈韦拉平或利托那韦增强的洛匹那韦（LPV/r）联合使用，但没有来自合并感染患者的临床数据。在健康志愿者中进行的奈韦拉平或LPV/r相互作用研究中获得了单次给药后贝达喹啉及其代谢产物M2的血浆浓度。采用非线性混合效应模型评价抗逆转录病毒药物对贝达喹啉和M2药代动力学的影响。通过模拟评价了可能的剂量调整。未发现奈韦拉平对贝达喹啉药代动力学的显著影响。LPV/r使贝达喹啉和M2清除率分别降低至未合并用药者的35%（相对标准误[RSE]，9.2%）和58%（RSE，8.4%）。由于预期LPV/r长期治疗期间暴露量增加近3倍（贝达喹啉）和2倍（M2），因此建议调整剂量进行评价。对于接受抗逆转录病毒治疗的耐多药结核病患者，有效、安全的贝达喹啉给药非常重要。建模结果表明，贝达喹啉可以与奈韦拉平联合给药，无需调整剂量。预计LPV/r联合给药期间贝达喹啉和M2水平升高可能是一个安全性问题，建议进行仔细监测。正在收集合并感染患者的进一步数据，以确定是否需要调整剂量。
Concomitant treatment of tuberculosis (TB) and HIV is recommended and improves outcomes. Bedaquiline is a novel drug for the treatment of multidrug-resistant (MDR) TB; combined use with antiretroviral drugs, nevirapine, or ritonavir-boosted lopinavir (LPV/r) is anticipated, but no clinical data from coinfected patients are available. Plasma concentrations of bedaquiline and its M2 metabolite after single doses were obtained from interaction studies with nevirapine or LPV/r in healthy volunteers. The antiretrovirals' effects on bedaquiline and M2 pharmacokinetics were assessed by nonlinear mixed-effects modeling. Potential dose adjustments were evaluated with simulations. No significant effects of nevirapine on bedaquiline pharmacokinetics were identified. LPV/r decreased bedaquiline and M2 clearances to 35% (relative standard error [RSE], 9.2%) and 58% (RSE, 8.4%), respectively, of those without comedication. As almost 3-fold (bedaquiline) and 2-fold (M2) increases in exposures during chronic treatment with LPV/r are expected, dose adjustments are suggested for evaluation. Efficacious, safe bedaquiline dosing for MDR-TB patients receiving antiretrovirals is important. Modeling results suggest that bedaquiline can be coadministered with nevirapine without dose adjustments. The predicted elevation of bedaquiline and M2 levels during LPV/r coadministration may be a safety concern, and careful monitoring is recommended. Further data are being collected in coinfected patients to determine whether dose adjustments are needed.