Population pharmacokinetics of enrofloxacin and florfenicol in the giant danio (Devario aequipinnatus) following oral administration of both antibiotics and bath administration of enrofloxacin

Abstract

The lack of pharmacokinetic and drug exposure data, even for commonly utilized antibiotics, in freshwater ornamental teleost fish species magnifies the difficulties in treating bacterial pathogens. This study aimed to determine the population pharmacokinetics of enrofloxacin and florfenicol and to predict their probability of target attainment for giant danio (Devario aequipinnatus), a close relative of the commercially and biomedically important zebra danio (Danio rerio). Enrofloxacin was dosed orally at 8 mg/kg or via bath at 10 mg/L in 95 fish, and florfenicol orally at 60 mg/kg in 56 fish. Informative sampling times were identified by optimal design analysis. Drug concentrations in blood and muscle homogenate were quantified by LC-MS/MS and modelled by population pharmacokinetics. Monte Carlo simulations were used to predict the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment. The apparent total clearance was 1.17 mL/h (33.9% coefficient of variation [CV] for between animal variability) for enrofloxacin and 1.89 mL/h (20.9% CV) for florfenicol. The ratio of drug exposure in muscle homogenate compared to that in plasma was 1.61 (33.3% CV) for enrofloxacin and 0.782 (19.4% CV) for florfenicol. Oral florfenicol at 60 mg/kg robustly covered MICs up to 2 to 4 mg/L, depending on the PK/PD target. While oral enrofloxacin (8 mg/kg) robustly covered MICs up to 0.125 to 0.5 mg/L, bath dosing at 10 mg/L for 5 or 10 h only covered MICs up to 0.0156 to 0.125 mg/L. These Monte Carlo simulations provided guidance on the range of MICs that result in high probabilities of successful treatment.