Cytokine-Mediated Systemic Adverse Drug Reactions in a Drug-Drug Interaction Study of Dolutegravir With Once-Weekly Isoniazid and Rifapentine
Cytokine-Mediated Systemic Adverse Drug Reactions in a Drug-Drug Interaction Study of Dolutegravir With Once-Weekly Isoniazid and Rifapentine
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DOI：
10.1093/cid/ciy082
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发表时间：
2018-07-15
影响因子：
11.8
通讯作者：
Kumar, Parag
中科院分区：
文献类型：
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作者：
Brooks, Kristina M.;George, Jomy M.;Kumar, Parag
背景资料。每周服用一次异烟肼和利福喷丁，为期3个月，是人类免疫缺陷病毒感染者和潜在结核病感染者的一种治疗选择。本研究旨在研究该方案与一线抗逆转录病毒药物多洛替格雷之间的药代动力学药物-药物相互作用。这是一项在健康志愿者中进行的单中心、开放标记、固定序列的药物-药物相互作用研究。受试者每天单独口服多洛替格雷50 mg(第1-4天)，同时每周服用一次异烟肼900 mg、利福喷丁900 mg和吡哆醇50 mg(第5-19天)。分别于第4、14、19天测定多洛替格雷浓度，第19天测定利福喷丁、25-去乙酰利福喷丁和异烟肼浓度。在选定的时间点检测细胞因子和抗异烟肼抗体。在服用第三剂异烟肼-利福喷丁后，4名受试者中有2名出现流感样综合征和转氨酶水平升高，研究终止。干扰素-γ、CXCL10、C-反应蛋白和其他细胞因子水平的显著升高与症状有时间上的联系。抗药物抗体检出较少。在第14天，多洛替格韦曲线下面积(AUC)减少了46%(90%可信区间，27-110%；P=.13)。第19天的利福喷丁和25-去乙酰利福喷丁水平与参考数据相当，而异烟肼的AUC在发生中毒的受试者中高出约67%-92%。多洛替格列韦与每周一次的异烟肼-利福喷丁联合使用导致了由内源性细胞因子释放介导的意想不到的严重毒性。进一步的研究是必要的，以检查联合应用这些药物的安全性和有效性。
Background. Once-weekly isoniazid and rifapentine for 3 months is a treatment option in persons with human immunodeficiency virus and latent tuberculosis infection. This study aimed to examine pharmacokinetic drug-drug interactions between this regimen and dolutegravir, a first-line antiretroviral medication.Methods. This was a single-center, open-label, fixed-sequence, drug-drug interaction study in healthy volunteers. Subjects received oral dolutegravir 50 mg once daily alone (days 1-4) and concomitantly with once-weekly isoniazid 900 mg, rifapentine 900 mg, and pyridoxine 50 mg (days 5-19). Dolutegravir concentrations were measured on days 4, 14, and 19, and rifapentine, 25-desacetyl-rifapentine, and isoniazid concentrations were measured on day 19. Cytokines and antidrug antibodies to isoniazid and rifapentine were examined at select time points.Results. The study was terminated following the development of flu-like syndrome and elevated aminotransferase levels in 2 of 4 subjects after the third isoniazid-rifapentine dose. Markedly elevated levels of interferon-gamma, CXCL10, C-reactive protein, and other cytokines were temporally associated with symptoms. Antidrug antibodies were infrequently detected. Dolutegravir area under the curve (AUC) was decreased by 46% (90% confidence interval, 27-110%; P=.13) on day 14. Rifapentine and 25-desacetyl rifapentine levels on day 19 were comparable to reference data, whereas isoniazid AUCs were approximately 67%-92% higher in the subjects who developed toxicities.Conclusions. The combined use of dolutegravir with once-weekly isoniazid-rifapentine resulted in unexpected and serious toxicities that were mediated by endogenous cytokine release. Additional investigations are necessary to examine the safety and efficacy of coadministering these medications.