Population Pharmacokinetics of Difloxacin in Crucian Carp (Carassius auratus) after a Single Oral Administration

SIMPLE SUMMARY: Crucian carp (Carassius auratus) is a freshwater fish that is popular due to its high nutritional value and delicious taste. It has become one of the most commonly farmed fish species, particularly in China. With the rapid development of intensive aquaculture, fish are becoming increasingly vulnerable to various pathogens that can cause significant economic losses. To reduce these losses, treatment with effective antibacterials is necessary. Although not approved in China, difloxacin is being used extensively in an extra-label manner to treat infections in aquaculture. However, the dosage guidelines specific to fish have not been established, resulting in the extrapolation of mammalian dosing regimens. Because fish are poikilotherms with unique physiologies and anatomies, dosing regimens intended for mammals may not be appropriate for them. In this research paper, we have employed a sparse sampling method and non-linear mixed effect modeling to develop population pharmacokinetics models. In addition, we have determined the values of the PK/PD parameter (free AUC/MIC) by utilizing previously published MIC data. Based on the free AUC/MIC values calculated herein, the current oral dose of difloxacin (20 mg/kg body weight) might be not enough to treat infections in crucian carp. ABSTRACT: This study aimed to investigate the population pharmacokinetics of difloxacin in crucian carp (Carassius auratus) orally provided a single dose of 20 mg/kg body weight (BW). To achieve this, fish were sampled at various intervals using a sparse sampling strategy, and plasma samples were analyzed using the high-performance liquid chromatography (HPLC) method. Subsequently, naïve average data were analyzed using a non-compartmental method, and a population model was developed based on the nonlinear mixed effects approach. The covariate of BW and the relationship between covariances were sequentially incorporated into the population model. However, it was found that only covariance and not BW affected the population parameters. Therefore, the covariance model was taken as the final population model, which revealed that the typical values of the absorption rate constant (tvKa), apparent volume of distribution per bioavailability (tvV), and clearance rate per bioavailability (tvCl) were 1.18 1/h, 14.18 L/kg, and 0.20 L/h/kg, respectively. Based on the calculated free AUC/MIC values, the current oral dose of difloxacin (20 mg/kg BW) cannot generate adequate plasma concentrations to inhibit pathogens with MIC values above 0.83 μg/mL. Further study should be carried out to collect the pathogens from crucian carp and determine the MIC data of difloxacin against them. Pharmacodynamic experiments must also be further carried out to determine the optimal therapeutic dose for the treatment of Aeromonas hydrophila infection.