Interpretation of Drug Interactions between Dolutegravir and Artemether-Lumefantrine or Artesunate-Amodiaquine
Interpretation of Drug Interactions between Dolutegravir and Artemether-Lumefantrine or Artesunate-Amodiaquine
复制标题
多替拉韦与蒿甲醚-卢美芴或青蒿琥酯-阿莫地喹之间药物相互作用的解释
DOI：
--
复制
发表时间：
2019
影响因子：
4.9
通讯作者：
G. Maartens
中科院分区：
文献类型：
--
作者：
C. G. Banda;K. Barnes;G. Maartens
Walimbwa 及其同事研究了多替拉韦（一种抗逆转录病毒整合酶链转移抑制剂）与青蒿琥酯-阿莫地喹 (ASAQ) 和蒿甲醚-本芴醇 (AL) 之间的药物相互作用，这两种常用的基于青蒿素的疟疾联合疗法 (1)。鉴于基于多替拉韦的抗逆转录病毒疗法在艾滋病毒和疟疾流行的地区迅速被用作一线治疗，他们的研究具有公共卫生重要性。他们报告说，AL 和 ASAQ 与多替拉韦共同给药显着降低了多替拉韦的稳态谷浓度，并且 ASAQ 但不是 AL 也降低了多替拉韦的总体暴露量。我们同意他们对多替拉韦和 ASAQ 之间药物相互作用的解释，并同意他们的结论，即 ASAQ 对多替拉韦谷浓度的影响可能不会产生临床显着效果，因为抗疟治疗与多替拉韦在短时间内（3 天）联合给药，并且多替拉韦谷浓度高于 300 ng/ml，这是可接受的最低浓度 浓度源自 2b 期研究 (2)。然而，我们认为药物相互作用不太可能解释他们观察到的与 AL 共同给药 24 小时 (C24) 时多替拉韦谷浓度降低 37% 的现象。单独给药和与 AL 一起给药时，多替拉韦平均浓度随时间变化的图（参见其文章中的图 1）显示，在单独使用多替拉韦和多替拉韦-AL 期间，所有时间点的多替拉韦浓度几乎相同，但单独使用多替拉韦期间平均 C24 较高。单独使用多替拉韦期间的较高平均 C24 远高于平均给药前多替拉韦浓度，这与多替拉韦-AL 期间的给药前浓度和 C24 非常相似不同。在文章的讨论中，作者指出，观察到的 C24 差异“可能部分是由于某些参与者中多替拉韦 C24 的不明原因升高所致”。对这些有影响力的观察结果最可能的解释似乎是，在单独使用多替拉韦期间，一些参与者在 C24 样本之前服用了 24 小时剂量的多替拉韦，而研究人员并不知情。单独的浓度-时间图会提供丰富的信息。作者表示，参与者不太可能服用额外的剂量，因为参与者得到了明确的说明和确切的药片数量，“这排除了这种额外的摄入量。”然而，参与者并不总是完全遵守研究方案说明。我们在一项利奈唑胺药代动力学研究中遇到了类似的问题，即一些参与者在 C24 样本之前假定摄入了 24 小时剂量。Citation Banda CG、Barnes KI、Maartens G. 2019。多替拉韦与蒿甲醚苯芴或青蒿琥酯-阿莫地喹之间药物相互作用的解释。抗菌剂 Chemother 63：e00576-19。 https://doi.org/10.1128/AAC.00576-19。版权所有 © 2019 美国微生物学会。版权所有。地址与 Gary Maartens 的通讯地址：gary.maartens@uct.ac.za。作者回复参见https://doi.org/10.1128/AAC.00593-19。发表致编辑的信
Walimbwa and colleagues investigated drug-drug interactions between dolutegravir, an antiretroviral integrase strand transfer inhibitor, with artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL), two commonly used artemisinin-based combination therapies for malaria (1). Their study is of public health importance given the rapid uptake of dolutegravir-based antiretroviral therapy as first-line treatment in settings where both HIV and malaria are endemic. They reported that coadministration of AL and ASAQ with dolutegravir significantly lowered the steady-state trough concentrations of dolutegravir, and that ASAQ but not AL also reduced the overall dolutegravir exposure. We agree with their interpretation of a drug-drug interaction between dolutegravir and ASAQ and with their conclusion that the impact of ASAQ on dolutegravir trough concentrations would likely not result in a clinically significant effect, as antimalarial treatment is coadministered with dolutegravir over a short duration (3 days) and the dolutegravir trough concentrations were above 300 ng/ml, which is the accepted minimum concentration derived from a phase 2b study (2). However, we feel that a drug interaction is an unlikely explanation for their observed 37% decrease in dolutegravir trough concentrations at 24 h (C24) with coadministration of AL. The plot of dolutegravir mean concentrations over time, when administered alone and with AL (see Fig. 1 in their article), shows that dolutegravir concentrations at all time points were almost identical in the dolutegravir-alone and the dolutegravir-AL periods, except for higher mean C24 in the dolutegravir-alone period. This higher mean C24 in the dolutegravir-alone period was well above that of the mean predose dolutegravir concentration, unlike the dolutegravir-AL period in which predose concentrations and C24 were very similar. In the Discussion in their article, the authors state that the observed difference in C24 “may have been driven in part by an unexplained rise in dolutegravir C24 in some participants.” The most likely explanation for these influential observations appears to be that some participants in the dolutegravir-alone period took the 24-h dose of dolutegravir before the C24 sample without the knowledge of study personnel. Individual concentration-time plots would have been informative. The authors state that additional dose taken by participants was unlikely as participants were given clear instructions and exact numbers of pills, “which precluded such additional intake.” However, perfect adherence by participants to study protocol instructions does not always occur. We encountered a similar problem of presumed intake of the 24-h dose before the C24 sample by some participants in a study of linezolid pharmacokinetics with drugCitation Banda CG, Barnes KI, Maartens G. 2019. Interpretation of drug interactions between dolutegravir and artemetherlumefantrine or artesunate-amodiaquine. Antimicrob Agents Chemother 63:e00576-19. https://doi.org/10.1128/AAC.00576-19. Copyright © 2019 American Society for Microbiology. All Rights Reserved. Address correspondence to Gary Maartens, gary.maartens@uct.ac.za. For the author reply, see https://doi.org/10 .1128/AAC.00593-19. Published LETTER TO THE EDITOR