Population pharmacokinetics of rifampicin in adult patients with osteoarticular infections: interaction with fusidic acid

Abstract

Aims: Rifampicin represents the key antibiotic for the management of osteoarticular infections. An important pharmacokinetic variability has already been described, particularly for absorption and metabolism. All previous pharmacokinetic studies have been focused only on patients treated for tuberculosis. The objective of the present study was to describe a population pharmacokinetic model of rifampicin in patients with staphylococcal osteoarticular infections, which has not been investigated to date. Method: Rifampicin concentrations were collected retrospectively from 62 patients treated with oral rifampicin 300 mg three times daily. Plasma concentration–time data were analysed using NONMEM to estimate population pharmacokinetic parameters. Demographic data, infection characteristics and antibiotics taken in addition to rifampicin antibiotics were investigated as covariates. Results: A one-compartment model, coupled to a transit absorption model, best described the rifampicin data. Fusidic acid coadministration was identified as a covariate in rifampicin pharmacokinetic parameters. The apparent clearance and apparent central volume of distribution mean values [95% confidence interval (CI)] were 5.1 1 h–1 (1.2, 8.2 1 h–1)/23.8 l (8.9, 38.7 l) and 13.7 1 h–1 (10.6, 18.0 1 h–1)/61.1 1 (40.8, 129.0 1) for patients with and without administration of fusidic acid, respectively. Interindividual variability (95% CI) in the apparent clearance and apparent central volume of distribution were 72.9% (49.5, 86.0%) and 59.1% (5.5, 105.4%), respectively. Residual variability was 2.3 mg l–1 (1.6, 2.6 mg l–1). Conclusion: We developed the first population pharmacokinetic model of rifampicin in patients with osteoarticular infections. Our model demonstrated that fusidic acid affects rifampicin pharmacokinetics, leading to potential high drug exposure. This finding suggests that fusidic acid dosing regimens should be reconsidered.