Exposure to Rifampicin and its Metabolite 25-Deacetylrifampicin Rapidly Decreases During Tuberculosis Therapy.

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Clinical Pharmacokinetics Pub Date : 2025-03-01 Epub Date: 2025-01-27 DOI:10.1007/s40262-025-01479-3
Sylvain Goutelle, Olivier Bahuaud, Charlotte Genestet, Aurélien Millet, François Parant, Oana Dumitrescu, Florence Ader
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Abstract

Background and objective: Limited information is available on the pharmacokinetics of rifampicin (RIF) along with that of its active metabolite, 25-deacetylrifampicin (25-dRIF). This study aimed to analyse the pharmacokinetic data of RIF and 25-dRIF collected in adult patients treated for tuberculosis.

Methods: In adult patients receiving 10 mg/kg of RIF as part of a standard regimen for drug-susceptible pulmonary tuberculosis enrolled in the Opti-4TB study, plasma RIF and 25-dRIF concentrations were measured at various occasions. The RIF and 25-dRIF concentrations were modelled simultaneously by using a population approach. The area under the concentration-time curves of RIF and 25-dRIF were estimated on each occasion of therapeutic drug monitoring. Optimal RIF exposure, defined as an area under the concentration-time curve over 24 hours/minimum inhibitory concentration > 435, was assessed.

Results: Concentration data (247 and 243 concentrations of RIF and 25-dRIF, respectively) were obtained in 35 patients with tuberculosis (10 women, 25 men). Mycobacterium tuberculosis minimum inhibitory concentration ranged from 0.06 to 0.5 mg/L (median = 0.25 mg/L). The final model was a two-compartment model including RIF metabolism into 25-dRIF and auto-induction. Exposure to 25-dRIF was low, with a mean area under the concentration-time curve over 24 h ratio of 25-dRIF/RIF of 14 ± 6%. The area under the concentration-time curve over 24 h of RIF and 25-dRIF rapidly decreased during therapy, with an auto-induction half-life of 1.6 days. Optimal RIF exposure was achieved in only six (19.3%) out of 31 patients upon first therapeutic drug monitoring.

Conclusions: Exposure to both RIF and 25-dRIF rapidly decreased during tuberculosis therapy. The contribution of 25-dRIF to overall drug exposure was low. Attainment of the target area under the concentration-time curve over 24 hours/minimum inhibitory concentration for RIF was poor, supporting an increased RIF dosage as an option to compensate for auto-induction.

结核治疗期间暴露于利福平及其代谢物25-去乙酰利福平迅速减少。
背景和目的:关于利福平(RIF)及其活性代谢物25-去乙酰利福平(25-dRIF)的药代动力学信息有限。本研究旨在分析成人结核病患者中RIF和25-dRIF的药代动力学数据。方法:在Opti-4TB研究中,接受10 mg/kg RIF作为药物敏感肺结核标准治疗方案的成人患者中,在不同场合测量血浆RIF和25-dRIF浓度。采用种群法同时模拟RIF和25-dRIF浓度。在每次治疗药物监测时,估计RIF和25-dRIF浓度-时间曲线下的面积。评估最佳RIF暴露,定义为浓度-时间曲线下超过24小时的面积/最低抑制浓度bbbb435。结果:35例结核病患者(女性10例,男性25例)获得了RIF和25- drif的浓度数据(分别为247和243)。结核分枝杆菌最低抑菌浓度范围为0.06 ~ 0.5 mg/L(中位数为0.25 mg/L)。最终模型为双室模型,包括RIF代谢为25-dRIF和自动诱导。25-dRIF暴露较低,24 h浓度-时间曲线下的平均面积为14±6%。在治疗过程中,RIF和25-dRIF的24 h浓度-时间曲线下面积迅速减小,其自诱导半衰期为1.6 d。在第一次治疗药物监测中,31例患者中只有6例(19.3%)达到最佳RIF暴露。结论:在结核病治疗期间,RIF和25-dRIF暴露迅速减少。25-dRIF对总体药物暴露的贡献很低。在24小时以上的浓度-时间曲线下达到RIF的目标区域/最低抑制浓度较差,支持增加RIF剂量作为补偿自动诱导的选择。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
8.80
自引率
4.40%
发文量
86
审稿时长
6-12 weeks
期刊介绍: Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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