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Background and Objective <p>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.</p> Methods <p>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 &gt; 435, was assessed.</p> Results <p>Concentration data (247 and 243 concentrations of RIF and 25-dRIF, respectively) were obtained in 35 patients with tuberculosis (10 women, 25 men). <i>Mycobacterium tuberculosis</i> 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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月27日

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  • Sylvain Goutelle,
  • Olivier Bahuaud,
  • Charlotte Genestet,
  • Aurélien Millet,
  • François Parant,
  • Oana Dumitrescu,
  • Florence Ader,
  • F. Ader,
  • O. Bahuaud,
  • R. Bayaa,
  • A. Becker,
  • E. Braun,
  • P. Chabert,
  • P. Chauvelot,
  • C. Chedid,
  • A. Conrad,
  • O. Dumitrescu,
  • T. Ferry,
  • C. Genestet,
  • S. Goutelle,
  • E. Hodille,
  • J. Hoffmann,
  • C. Javaux,
  • G. Lina,
  • C. Pouderoux,
  • T. Perpoint,
  • S. Roux,
  • M. Simon,
  • F. Valour

摘要

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.