Effect of dosage regimen on plasma and milk distribution of danofloxacin in sheep

Danofloxacin can be utilized in varying dosage regimens for the treatment of infections caused by sensitive bacteria in sheep. However, its plasma and milk distribution may vary with different dosing strategies. Changes in the distribution of danofloxacin in plasma and milk could influence the pharmacodynamic efficacy of the drug and the residue levels in milk, potentially affecting both animal and human health. This study aimed to determine the pharmacokinetics of danofloxacin in plasma and milk, accumulation ratio, binding to plasma and milk proteins, withdrawal time for milk, and pharmacokinetic/pharmacodynamic parameters utilizing the minimum inhibitory concentration (MIC) threshold of ≤1 µg/mL and pharmacokinetic data obtained from this study. The study was conducted on 16 healthy, lactating Merino ewes (75-80 days post-lambing, weighing 65,07±6,17 kg) following a parallel pharmacokinetic design. The ewes were randomly divided into two groups to evaluate the pharmacokinetics of danofloxacin. Group 1 received danofloxacin at a dosage of 1,25 mg/kg, while Group 2 received 6 mg/kg, administered every 24 hours for 7 days. Concentrations in plasma and milk samples collected after the 1. and 7. (steady-state) doses were determined using high-performance liquid chromatography-UV. Pharmacokinetic parameters were analyzed using non-compartmental methods, and the withdrawal time for milk was calculated using WTM 1,4 software. Following the 7. dose, danofloxacin was detectable in plasma up to 24 and 48 hours for the 1,25 and 6 mg/kg doses respectively, and in milk up to 48 and 96 hours respectively. Dose-normalized plasma and milk Cmax and AUC0-24 values were similar between dosage groups after the 1. dose. However, at steady-state, dose-normalized Cmax and AUC0-∞ in plasma decreased with the 6 mg/kg dose compared to the 1,25 mg/kg dose, while they increased in milk. The (AUC0-∞)Milk/(AUC0-∞)Plasma ratio was significantly higher at the 6 mg/kg dose (17,68) compared to the 1,25 mg/kg dose (13,34). Accumulation ratio (R) for the 1,25 and 6 mg/kg doses was 0.82 and 0.80, respectively. The protein binding ratios of danofloxacin in plasma and milk were found to be 30.5±6.7% and 36.9±10.8%, demonstrating a dose-dependent decrease. The milk withdrawal time for residue levels corresponding to the MRL value of 30 µg/kg was determined to be 55,56 hours for the 1,25 mg/kg dose and 107,88 hours for the 6 mg/kg dose. Danofloxacin achieved optimal plasma and milk fAUC0-24/MIC ratios (>125) for bacteria with MIC values of ≤0,016 and ≤0,25 µg/mL for the 1,25 mg/kg dose, and ≤0,063 and ≤1 µg/mL for the 6 mg/kg dose. Clinicians should adjust dosage regimens according to the variations in plasma and milk distribution of danofloxacin and monitor residue levels in milk to ensure the drug's efficacy.