title: Pharmacological indices and pulmonary distribution of rifampicin after repeated oral administration in healthy foals.
abstract: BACKGROUND
  The 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.
  
  
  OBJECTIVE
  To 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.
  
  
  METHODS
  Controlled, randomised, two-period, crossover, repeated-dose study with an initial arm to measure disposition after i.v. administration of rifampicin.
  
  
  METHODS
  Pharmacokinetics 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 4β-OH-cholesterol:cholesterol ratios.
  
  
  RESULTS
  The distribution volume of rifampicin administered i.v. was ~0.85 L/kg. Terminal elimination half-life was ~11 h. Orally given rifampicin was slowly absorbed (Tmax, range: 2.5-8.0 h) and eliminated with apparent half-lives of ~6-8 h. Trough concentrations in ELF and BALC were 1.01 ± 0.20 μg/mL and 1.25 ± 0.29 μg/mL, respectively, after 10 mg/kg bwt rifampicin and 2.71 ± 1.25 μg/mL and 3.09 ± 1.63 μg/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 (AUC0-24 h) to minimum inhibitory concentration (MIC) were 145 and 322 h, respectively, for less susceptible strains of R. equi (MIC90: 0.5 μg/mL).
  
  
  CONCLUSIONS
  The clearance and bioavailability of rifampicin after repeated oral dosing were not evaluated.
  
  
  CONCLUSIONS
  Treatment with rifampicin at 10 mg/kg bwt administered once per day is suitable to generate drug concentrations above the MIC90in 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.
authors.affiliation: Department of Clinical Pharmacology, Centre of Drug Absorption and Transport (C_DAT), University Medicine of Greifswald, Greifswald, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Berlin
authors.affiliation: Lewitz Stud, Neustadt-Glewe, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kirschbaum
authors.affiliation: Veterinary Clinic for Horses, Destedt, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Spieckermann
authors.affiliation: Department of Clinical Pharmacology, Centre of Drug Absorption and Transport (C_DAT), University Medicine of Greifswald, Greifswald, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Oswald
authors.affiliation: Department of Clinical Pharmacology, Centre of Drug Absorption and Transport (C_DAT), University Medicine of Greifswald, Greifswald, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Keiser
authors.affiliation: Department of General Pharmacology, Centre of Drug Absorption and Transport (C_DAT), University Medicine of Greifswald, Greifswald, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Grube
authors.affiliation: Veterinary Clinic for Horses, Destedt, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Venner
authors.affiliation: Department of Clinical Pharmacology, Centre of Drug Absorption and Transport (C_DAT), University Medicine of Greifswald, Greifswald, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Siegmund
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D006207:Half-Life; D006736:Horses; D008168:Lung / Q000378:metabolism*; D011897:Random Allocation; D012293:Rifampin / Q000493:pharmacokinetics*
chemical_list: D000900:Anti-Bacterial Agents; D012293:Rifampin
keywords: PK/PD indices; foals; horse; lung distribution; pharmacokinetics; rifampicin