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  Discussion on Research: Dosage of Rifampin
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Posted on Sunday, Jan 15, 2017 - 10:34 am:

Equine Vet J. 2017 Jan 7. doi: 10.1111/evj.12662.
Pharmacological indices and pulmonary distribution of rifampicin after repeated oral administration in healthy foals.
Berlin S1, Kirschbaum A2, Spieckermann L3, Oswald S1, Keiser M1, Grube M4, Venner M3, Siegmund W1.
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BACKGROUND:
The treatment of equine lung infections by R. equi with rifampicin is empirically based because pharmacokinetic/pharmacodynamic (PK/PD) indices and pivotal clinical outcome data are not available.
OBJECTIVES:
Evaluation of pharmacokinetics and pulmonary distribution into epithelial lining fluid (ELF) and bronchoalveolar lavage cells (BALC) to predict antimicrobial activity in the lung using PK/PD-indices.
STUDY DESIGN:
Controlled, randomised, two-period, crossover, repeated-dose study with an initial arm to measure disposition after intravenous administration.
METHODS:
Pharmacokinetics and lung distribution were evaluated in 6 healthy foals treated with 10 mg/kg rifampicin intravenously (initial arm) and with repeated oral doses of 10 and 20 mg/kg once daily for 10 days (crossover arms). ELF and BALC were sampled by bronchoalveolar lavage 24 hours after the respective last oral dosing. Rifampicin and 25-O-desacetyl rifampicin were quantified using LC-MS/MS. Enzyme induction by rifampicin was confirmed by evaluation of the plasma 4β-OH-cholesterol/cholesterol-ratios.
RESULTS:
The distribution volume of intravenously administered rifampicin was ~ 0.85 l/kg and terminal elimination half-life ~ 11 hours. Orally given rifampicin was slowly absorbed (range for Tmax : 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 after 10 mg/kg rifampicin and 2.71 ± 1.25 μg/ml and 3.09 ± 1.63 μg/ml, respectively, after 20 mg/kg. The average AUC0-24 h /MIC ratios were 145 h and 322 h, respectively, for less susceptible R. equi strains (MIC90 = 0.5 μg/ml).
MAIN LIMITATIONS:
Clearance and bioavailability of rifampicin after repeated oral dosing were not evaluated.
CONCLUSIONS:
Treatment with 10 mg/kg rifampicin given once daily 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 treatment of R. equi lung infections.
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