Pharmacokinetic–pharmacodynamic modelling for the determination of optimal dosing regimen of florfenicol in Nile tilapia (Oreochromis niloticus) at different water temperatures and antimicrobial susceptibility levels

Abstract

Optimized dosing regimen is key to the effective use of antibacterials and to minimizing drug‐related side effects. The current study established a pharmacokinetic–pharmacodynamic (PK‐PD) model for the determination of optimal antibacterial dosing regimen in fish taken into consideration the temperature‐dependent PK and the pathogen‐dependent antimicrobial susceptibility, using florfenicol (FF) in Nile tilapia as an example. The calculated optimal dosages significantly varied by temperature and target MIC levels, ranging from 2.23 (MIC 1 µg/ml at 24°C) to 34.88 mg kg−1 day−1 (MIC 4 µg/ml at 32°C). The appropriateness of the calculated dosages was successfully verified by the in vivo studies. After 5 days of oral administration of the calculated optimal dosage at 24°C, the predicted plasma drug values were in line with the mean observed Cmin(ss) while at 28 and 32°C underestimation of the Cmin(ss) in a dose‐dependent manner was observed and likely due to the occurrence of non‐linear PK at high dosages. The averaged serum protein binding of FF was 19.1%. Our results demonstrated the appropriateness and clinical applicability of the developed PK‐PD approach for the determination of optimal dosing regimens at given temperatures and MICs. Saturation metabolism and PK non‐linearity of FF in tilapia warrant further study.

Determination of Optimal Doses and Minimum Effective Concentrations of Tricaine Methanesulfonate, 2-Phenoxyethanol and Eugenol for Laboratory Managements in Nile Tilapia (Oreochromis niloticus)

“…Unlike antibacterial drugs, where the relationship between pharmacokinetic–pharmacodynamic (PK–PD) index and therapeutic outcome exists and permits the use of PK–PD modeling to determine the optimal dosage [ 8 ], the optimal dose of the anesthetic agent is conventionally determined by the dose titration approach in which the fish are exposed to different doses of anesthetics for varying periods of time. The dose that could provide an appropriate time frame for scientific procedure with rapid induction and recovery time would be considered optimal (see the Materials and Methods section).…”

Temperature‐dependent pharmacokinetics of trichlorfon in common carp (Cyprinus carpio L.) after bath immersion therapy

“…Increasing the temperature accelerates drug depletion, as shown by the shortened tissue t 1/2 . Rairat et al, (2019) found that a change in temperature led to a change in florfenicol distribution in adult O . niloticus , which is consistent with this result, indicating that temperature is an important factor for explaining variations in the TCF PK process.…”

Temperature-Dependent Residue Depletion Regularities of Tiamulin in Nile Tilapia (Oreochromis niloticus) Following Multiple Oral Administrations

“…Moreover, in aquatic animals, the residue depletion and WT of a drug can be deeply affected by environmental factors, such as temperature, pH, and salinity (oxytetracycline in tilapia) of water in which the animals are raised (20,21). As far as temperature is concerned, because fish are heterothermic animals, a large number of researches showed that the absorption, distribution, biotransformation, and excretion of different drugs in different fish can be seriously affected by temperature, such as florfenicol in Nile tilapia (22,23), doxycycline in grass carp (24), florfenicol amine in crucian carp (25), and enrofloxacin and its metabolite ciprofloxacin in turbot (26). Therefore, the goal of this study was to explore the residue characterization and acquire the WT of tiamulin in Nile tilapia plasma, muscle plus skin, liver, kidney, and gill at three different water temperatures.…”