Rifampicin is a first-line anti-TB drug. The objectives of this analysis were to evaluate the population pharmacokinetics of rifampicin and its partly active metabolite, 25-deacetyl-rifampicin, with and without isoniazid, and to identify covariates that may explain variability in their disposition under steady-state conditions.Methods
Thirty-four healthy Asian subjects were randomized to receive rifampicin (600 mg) or rifampicin (600 mg)/isoniazid (300 mg) daily for 14 days. After a 14 day washout, subjects were switched over to rifampicin (600 mg)/isoniazid (300 mg) or rifampicin (600 mg) daily. Plasma concentration–time data were analysed using NONMEM to estimate population pharmacokinetic parameters and evaluate relationships between parameters and demographic factors, and metabolic enzyme, transporter and transcriptional regulator genotypes. Allometric scaling of clearance and volume of distribution terms based on body weight was applied.Results
A one-compartment model in which absorption was described by a transit absorption model best described the rifampicin data. 25-Deacetyl-rifampicin pharmacokinetic data were best described by a two-compartment model linked to the rifampicin model. None of the investigated covariates significantly influenced the disposition of rifampicin and 25-deacetyl-rifampicin. The apparent clearance of rifampicin and 25-deacetyl-rifampicin was estimated at 10.3 [relative standard error (RSE) 5.6%] and 95.8 (RSE 10%) L/h, respectively, for 70 kg adults.Conclusions
The pharmacokinetics of rifampicin and its main metabolite were characterized. Prospective studies with a larger number of participants, including patients, are needed to validate the results of this study.