Description:
<jats:title>Summary</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The treatment of equine lung infections by <jats:italic>Rhodococcus equi</jats:italic> with rifampicin is empirically based because pharmacokinetic/pharmacodynamic (<jats:styled-content style="fixed-case">PK</jats:styled-content>/<jats:styled-content style="fixed-case">PD</jats:styled-content>) indices and pivotal clinical outcome data are not available.</jats:p></jats:sec><jats:sec><jats:title>Objectives</jats:title><jats:p>To evaluate the pharmacokinetics and pulmonary distribution of rifampicin into epithelial lining fluid (<jats:styled-content style="fixed-case">ELF</jats:styled-content>) and bronchoalveolar lavage cells (<jats:styled-content style="fixed-case">BALC</jats:styled-content>) to predict antimicrobial activity in the lung using <jats:styled-content style="fixed-case">PK</jats:styled-content>/<jats:styled-content style="fixed-case">PD</jats:styled-content> indices.</jats:p></jats:sec><jats:sec><jats:title>Study design</jats:title><jats:p>Controlled, randomised, two‐period, crossover, repeated‐dose study with an initial arm to measure disposition after i.v. administration of rifampicin.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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). <jats:styled-content style="fixed-case">ELF</jats:styled-content> and <jats:styled-content style="fixed-case">BALC</jats:styled-content> 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‐<jats:styled-content style="fixed-case">OH</jats:styled-content>‐cholesterol:cholesterol ratios.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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 (T<jats:sub>max</jats:sub>, range: 2.5–8.0 h) and eliminated with apparent half‐lives of ~6–8 h. Trough concentrations in <jats:styled-content style="fixed-case">ELF</jats:styled-content> and <jats:styled-content style="fixed-case">BALC</jats:styled-content> 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 (<jats:styled-content style="fixed-case">AUC</jats:styled-content><jats:sub>0−24 h</jats:sub>) to minimum inhibitory concentration (<jats:styled-content style="fixed-case">MIC</jats:styled-content>) were 145 and 322 h, respectively, for less susceptible strains of <jats:italic>R. equi</jats:italic> (<jats:styled-content style="fixed-case">MIC</jats:styled-content><jats:sub>90</jats:sub>: 0.5 μg/mL).</jats:p></jats:sec><jats:sec><jats:title>Main limitations</jats:title><jats:p>The clearance and bioavailability of rifampicin after repeated oral dosing were not evaluated.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Treatment with rifampicin at 10 mg/kg bwt administered once per day is suitable to generate drug concentrations above the <jats:styled-content style="fixed-case">MIC</jats:styled-content><jats:sub>90</jats:sub> in the <jats:styled-content style="fixed-case">ELF</jats:styled-content> and <jats:styled-content style="fixed-case">BALC</jats:styled-content> of foals. Future clinical studies with rifampicin in combination with macrolide antibiotics with low drug interaction potential are required to translate the <jats:styled-content style="fixed-case">PK</jats:styled-content>/<jats:styled-content style="fixed-case">PD</jats:styled-content> indices into protocols for the treatment of <jats:italic>R. equi</jats:italic> lung infections.</jats:p></jats:sec>