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

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.