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



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.



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).



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.
Service de Pharmacologie Clinique et Pharmacovigilance, Hôpital de la Timone, Marseille, 264 rue saint pierre, 13385, Marseille, France.|Aix Marseille Université, Pharmacologie intégrée et interface clinique et industrielle, Institut des Neurosciences Timone - CNRS 7289, 27 boulevard jean moulin, Marseille, 13385, France.
Amélie
A
Marsot
Pôle des Maladies Infectieuses et Tropicales Clinique et Biologique, Service de Maladies Infectieuses, Fondation IHU Méditerranée Infection, Centre Hospitalo-Universitaire Conception, 147, Boulevard Baille, 13385, Marseille cedex 05, France.
Amelie
A
Ménard
Service de Pharmacologie Clinique et Pharmacovigilance, Hôpital de la Timone, Marseille, 264 rue saint pierre, 13385, Marseille, France.|Aix Marseille Université, Pharmacologie intégrée et interface clinique et industrielle, Institut des Neurosciences Timone - CNRS 7289, 27 boulevard jean moulin, Marseille, 13385, France.
Julien
J
Dupouey
Service de Pharmacologie Clinique et Pharmacovigilance, Hôpital de la Timone, Marseille, 264 rue saint pierre, 13385, Marseille, France.
Cedric
C
Muziotti
Service de Pharmacologie Clinique et Pharmacovigilance, Hôpital de la Timone, Marseille, 264 rue saint pierre, 13385, Marseille, France.|Aix Marseille Université, Pharmacologie intégrée et interface clinique et industrielle, Institut des Neurosciences Timone - CNRS 7289, 27 boulevard jean moulin, Marseille, 13385, France.
Romain
R
Guilhaumou
Service de Pharmacologie Clinique et Pharmacovigilance, Hôpital de la Timone, Marseille, 264 rue saint pierre, 13385, Marseille, France.|Aix Marseille Université, Pharmacologie intégrée et interface clinique et industrielle, Institut des Neurosciences Timone - CNRS 7289, 27 boulevard jean moulin, Marseille, 13385, France.
Olivier
O
Blin
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001850:Bone Diseases, Infectious / Q000188:drug therapy / Q000382:microbiology; D005260:Female; D005672:Fusidic Acid / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007592:Joint Diseases / Q000188:drug therapy / Q000382:microbiology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D012189:Retrospective Studies; D012293:Rifampin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013203:Staphylococcal Infections; D055815:Young Adult
D000900:Anti-Bacterial Agents; D005672:Fusidic Acid; D012293:Rifampin
NONMEM; fusidic acid; osteoarticular infections; population pharmacokinetics; rifampicin