Impact of rifampicin on the pharmacokinetics of clarithromycin and 14-hydroxy clarithromycin in patients with multidrug combination therapy for pulmonary Mycobacterium avium complex infection
Impact of rifampicin on the pharmacokinetics of clarithromycin and 14-hydroxy clarithromycin in patients with multidrug combination therapy for pulmonary Mycobacterium avium complex infection
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DOI：
10.1016/j.jiac.2021.10.003
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发表时间：
2021-11-14
影响因子：
2.2
通讯作者：
Hasegawa, Naoki
中科院分区：
文献类型：
--
作者：
Iketani, Osamu;Komeya, Akari;Hasegawa, Naoki
简介：克拉霉素（CAM）、乙胺丁醇（EB）和利福平（RFP）联合治疗肺鸟分枝杆菌复体（MAC）感染；然而，由于rfp介导的CYP3A活性的诱导，血清CAM浓度降低。因此，我们研究了CAM、14-羟基克拉霉素（14-OH CAM）、EB和RFP在接受这三种药物联合治疗的患者中的药代动力学。方法：开始CAM单药治疗，2周后加EB， 2周后加RFP。测定给药前及给药后第14、28、42天2、4、6、12、24 h血清CAM、14- oh CAM、EB和RFP浓度，并计算药代动力学参数。结果：与CAM单药治疗相比，RFP联合给药后0 ~ 12 h， CAM的曲线下中位面积（AUC）下降92.1%[分别为1.7（四分位间距[IQR]， 1.4 ~ 1.8） mu g.h/mL和21.5（四分位间距[IQR]， 17.7 ~ 32.3） mu g.h/mL]。相比之下，同时给予RFP [9.1 (IQR, 7.9-10.9) mu g.h/mL]和CAM单药治疗[8.2 (IQR, 6.3-9.3) mu g.h/mL]的14-OH CAM的中位AUC无显著差异。CAM+EB联合治疗时，CAM和14-OH CAM的auc无变化。结论：RFP联合CAM治疗肺部MAC感染时，CAM血药浓度明显降低，活性代谢物14-OH CAM血药浓度升高，但不显著。我们的研究结果表明，在治疗肺部MAC感染时，需要重新考虑CAM和RFP联合治疗，可能需要调整剂量。
Introduction: Clarithromycin (CAM), ethambutol (EB), and rifampicin (RFP) combination therapy is used to treat pulmonary Mycobacterium avium complex (MAC) infection; however, serum CAM concentration decreases due to RFP-mediated induction of CYP3A activity. Therefore, we investigated the pharmacokinetics of CAM, 14-hy-droxy clarithromycin (14-OH CAM), EB, and RFP in patients receiving this three-drug combination therapy.Methods: CAM monotherapy was started, EB was added 2 weeks later, and RFP was added 2 weeks after that. Serum CAM, 14-OH CAM, EB, and RFP concentrations were measured before and at 2, 4, 6, and 12 or 24 h after administration on days 14, 28, and 42, and pharmacokinetic parameters were calculated.Results: Median area under the curve (AUC) of CAM decreased by 92.1% from 0 to 12 h after concomitant administration of RFP compared with CAM monotherapy [1.7 (interquartile range [IQR], 1.4-1.8) mu g.h/mL vs. 21.5 (IQR, 17.7-32.3) mu g.h/mL, respectively]. In contrast, median AUC of 14-OH CAM was not significantly different between concomitant administration of RFP [9.1 (IQR, 7.9-10.9) mu g.h/mL] and CAM monotherapy [8.2 (IQR, 6.3-9.3) mu g.h/mL]. AUCs of CAM and 14-OH CAM did not change in CAM+EB combination therapy.Conclusions: When RFP is combined with CAM in the treatment of pulmonary MAC infection, the blood concentration of CAM significantly decreased and that of the active metabolite 14-OH CAM increased, but not significantly. Our results suggest that combination therapy with CAM and RFP needs to be reconsidered and may require dose modification in the treatment of pulmonary MAC infection.