Pharmacological indices and pulmonary distribution of rifampicin after repeated oral administration in healthy foals

BackgroundThe treatment of equine lung infections by Rhodococcus equi with rifampicin is empirically based because pharmacokinetic/pharmacodynamic (PK/PD) indices and pivotal clinical outcome data are not available. ObjectivesTo evaluate the pharmacokinetics and pulmonary distribution of rifampicin into epithelial lining fluid (ELF) and bronchoalveolar lavage cells (BALC) to predict antimicrobial activity in the lung using PK/PD indices. Study designControlled, randomised, two-period, crossover, repeated-dose study with an initial arm to measure disposition after i.v. administration of rifampicin. MethodsPharmacokinetics and lung distribution were evaluated in six healthy foals treated with 10 mg/kg bwt rifampicin i.v. (initial arm) and with repeated oral doses of rifampicin at 10 mg/kg bwt and 20 mg/kg bwt once per day for 10 days (crossover arms). ELF and BALC were sampled by bronchoalveolar lavage 24 h after the last oral dosing. Rifampicin and 25-O-desacetyl rifampicin were quantified using liquid chromatography tandem-mass spectrometry. Enzyme induction by rifampicin was confirmed by evaluation of plasma 4-OH-cholesterol:cholesterol ratios. ResultsThe distribution volume of rifampicin administered i.v. was similar to 0.85 L/kg. Terminal elimination half-life was similar to 11 h. Orally given rifampicin was slowly absorbed (T-max, range: 2.5-8.0 h) and eliminated with apparent half-lives of similar to 6-8 h. Trough concentrations in ELF and BALC were 1.01 0.20 g/mL and 1.25 0.29 g/mL, respectively, after 10 mg/kg bwt rifampicin and 2.71 +/- 1.25 g/mL and 3.09 +/- 1.63 g/mL, respectively, after 20 mg/kg bwt rifampicin. The average ratios of area under the plasma concentration time curve during an administration interval of 24 h (AUC(0-24 h)) to minimum inhibitory concentration (MIC) were 145 and 322 h, respectively, for less susceptible strains of R. equi (MIC90: 0.5 g/mL). Main limitationsThe clearance and bioavailability of rifampicin after repeated oral dosing were not evaluated. ConclusionsTreatment with rifampicin at 10 mg/kg bwt administered once per day is suitable to generate drug concentrations above the MIC90 in the ELF and BALC of foals. Future clinical studies with rifampicin in combination with macrolide antibiotics with low drug interaction potential are required to translate the PK/PD indices into protocols for the treatment of R. equi lung infections.