Janssen Research and Development LLC, Titusville, NJ, USA.
HIV Med. 2013 Aug;14(7):421-9. doi: 10.1111/hiv.12019. Epub 2013 Feb 26.
Etravirine is a substrate and inducer of cytochrome P450 (CYP) 3A and a substrate and inhibitor of CYP2C9 and CYPC2C19. Darunavir/ritonavir is a substrate and inhibitor of CYP3A. Artemether and lumefantrine are primarily metabolized by CYP3A; artemether is also metabolized to a lesser extent by CYP2B6, CYP2C9 and CYP2C19. Artemether has an active metabolite, dihydroartemisinin. The objective was to investigate pharmacokinetic interactions between darunavir/ritonavir or etravirine and arthemether/lumefrantrine.
This single-centre, randomized, two-way, two-period cross-over study included 33 healthy volunteers. In panel 1, 17 healthy volunteers received two treatments (A and B) in random order, with a washout period of 4 weeks between treatments: treatment A: artemether/lumefantrine 80/480 mg alone, in a 3-day course; treatment B: etravirine 200 mg twice a day (bid) for 21 days with artemether/lumefantrine 80/480 mg from day 8 (a 3-day treatment course). In panel 2, another 16 healthy volunteers received two treatments, similar to those in panel 1 but instead of etravirine, darunavir/ritonavir 600/100 mg bid was given.
Overall, 28 of the 33 volunteers completed the study. Co-administration of etravirine reduced the area under the plasma concentration-time curve (AUC) of artemether [by 38%; 90% confidence interval (CI) 0.48-0.80], dihydroartemisinin (by 15%; 90% CI 0.75-0.97) and lumefantrine (by 13%; 90% CI 0.77-0.98) at steady state. Co-administration of darunavir/ritonavir reduced the AUC of artemether (by 16%; 90% CI 0.69-1.02) and dihydroartemisinin (by 18%; 90% CI 0.74-0.91) but increased lumefantrine (2.75-fold; 90% CI 2.46-3.08) at steady state. Co-administration of artemether/lumefantrine had no effect on etravirine, darunavir or ritonavir AUC. No drug-related serious adverse events were reported during the study.
Co-administration of etravirine with artemether/lumefantrine may lower the antimalarial activity of artemether and should therefore be used with caution. Darunavir/ritonavir can be co-administered with artemether/lumefantrine without dose adjustment but should be used with caution.
依曲韦林是细胞色素 P450（CYP）3A 的底物和诱导剂，也是 CYP2C9 和 CYP2C19 的底物和抑制剂。达鲁那韦/利托那韦是 CYP3A 的底物和抑制剂。青蒿素和本芴醇主要通过 CYP3A 代谢；青蒿素也可被 CYP2B6、CYP2C9 和 CYP2C19 少量代谢。青蒿素有一种活性代谢物，二氢青蒿素。本研究旨在探讨达鲁那韦/利托那韦或依曲韦林与青蒿素和本芴醇之间的药代动力学相互作用。
这是一项单中心、随机、双盲、两周期交叉研究，纳入了 33 名健康志愿者。在第 1 组中，17 名健康志愿者随机接受两种治疗（A 和 B），两种治疗之间有 4 周的洗脱期：治疗 A：青蒿素和本芴醇 80/480mg 单独使用，疗程 3 天；治疗 B：依曲韦林 200mg 每日两次（bid）治疗 21 天，从第 8 天（3 天疗程）开始合用青蒿素和本芴醇 80/480mg。在第 2 组中，另 16 名健康志愿者接受了两种与第 1 组相似的治疗，但替代依曲韦林的是达鲁那韦/利托那韦 600/100mg bid。
总体而言，33 名志愿者中有 28 名完成了研究。依曲韦林联合用药使青蒿素的血浆浓度-时间曲线下面积（AUC）降低[38%；90%置信区间（CI）0.48-0.80]，二氢青蒿素（15%；90%CI 0.75-0.97）和本芴醇（13%；90%CI 0.77-0.98）在稳态时。达鲁那韦/利托那韦联合用药使青蒿素 AUC 降低[16%；90%CI 0.69-1.02]和二氢青蒿素（18%；90%CI 0.74-0.91），但使本芴醇 AUC 增加[2.75 倍；90%CI 2.46-3.08]在稳态时。青蒿素和本芴醇联合用药对依曲韦林、达鲁那韦或利托那韦 AUC 没有影响。研究期间无药物相关严重不良事件报告。
依曲韦林与青蒿素和本芴醇合用可能降低青蒿素的抗疟活性，因此应谨慎使用。达鲁那韦/利托那韦可与青蒿素和本芴醇联合使用而无需调整剂量，但应谨慎使用。
