Development and Application of a Water Temperature Related Physiologically Based Pharmacokinetic Model for Enrofloxacin and Its Metabolite Ciprofloxacin in Rainbow Trout

Abstract

Enrofloxacin (ENR) has been approved for the treatment of infections in aquaculture, but it may cause tissue residue. This research aimed to develop and validate a water temperature related PBPK model, including both ENR and ciprofloxacin (CIP), in rainbow trout, and to predict further their residue concentrations and the withdrawal periods for ENR at different water temperatures. With the published concentrations data, a flow-limited PBPK model including both ENR and CIP sub-models was developed to predict ENR and CIP concentrations in tissues and plasma/serum after intravenous, oral, or immersion administration. A Monte Carlo simulation including 500 iterations was further incorporated into this model. Based on the model and Monte Carlo analysis, the withdrawal intervals were estimated for different dosage regimens and at different water temperatures, ranging from 80 to 272 degree-days. All of these values were shorter than the labeled withdrawal period (500 degree-days) in fish. This model provided a useful tool for predicting the tissue residues of ENR and CIP in rainbow trout under different dosage regimens and at different water temperatures.

Development and application of a physiologically based pharmacokinetic model for orbifloxacin in crucian carp (Carassius auratus)

“…Initially, we used a two‐compartment model to simulate the absorption of orbifloxacin after intramuscular injection; however, satisfactory predictions could not be obtained, so we finally chose the current one‐compartment model (Yang et al, 2013). A water temperature‐related PBPK model was established in rainbow trout (Yang et al, 2021), which could adequately predict the concentrations of enrofloxacin and its metabolite ciprofloxacin in rainbow trout reared at a wide range of water temperatures (5–16°C). Essentially, the current model was also temperature‐related because the cardiac output depended on water temperature (Barron et al, 1987).…”

“…The physiological and anatomical parameters were derived from previous fish PBPK models (Yang et al, 2013(Yang et al, , 2021 and presented in Table 2. The tissue weight and blood flow were abbreviated to V cx and Q cx , respectively, and expressed as BW and cardiac output fractions.…”

“…In recent years, there has been an increase in the applications of physiologically based pharmacokinetic (PBPK) models to predict veterinary drug residues (Buur et al, 2009; Craigmill, 2003; Leavens et al, 2012; Li et al, 2019; Xu et al, 2020; Yang et al, 2019, 2021; Yang, Yang, Shi, et al, 2018; Zeng et al, 2019). PBPK models are predictive and based on mass‐balance equations defined by physiological mechanisms than the traditional post‐slaughter monitoring methods (Yang, Yang, Shi, et al, 2018).…”

Apply a Physiologically Based Pharmacokinetic Model to Promote the Development of Enrofloxacin Granules: Predict Withdrawal Interval and Toxicity Dose

“…In this paper, similarly to what Yang et al (2021) reported, firstly the 1000 virtual individuals with different physiological parameters were simulated, by giving a default 10% coefficients of variance (CVs) to the sensitive parameters [ 20 ]. However, the calculated WTs in the edible tissues were significantly shorter than the measured WTs.…”

“…Then, these values were calculated, after rounding up to the next whole day, according to WT estimation criteria [ 17 ]. Reportedly, the WT values that were calculated by the EMA’s method could keep consistent with the values, using one MC simulation [ 20 , 23 ]. Therefore, using one MC analysis, with 1000 iterations for each tissue, is sufficient to predict the WTs of the ENR granules in tissues.…”