# Pharmacokinetic and Pharmacodynamic Modeling of Enrofloxacin and Its Metabolite Ciprofloxacin in Pregnant Goats

## TL;DR

This study models how enrofloxacin and its metabolite ciprofloxacin move in pregnant goats and reach the fetus, recommending an optimal dosage to treat infections safely.

## Contribution

The study is the first to model the pharmacokinetics and placental transfer of enrofloxacin and ciprofloxacin in pregnant goats.

## Key findings

- Both enrofloxacin and ciprofloxacin cross the placenta in goats.
- A dose of 10 mg/kg/day of enrofloxacin is recommended for treating infections in pregnant goats.
- Tentative epidemiological cutoffs for coagulase-negative staphylococci isolates were calculated at 0.25 and 0.5 mg/L.

## Abstract

Pharmacokinetics studies how drugs move in the body between the blood and different organs and tissues. When a treatment is given to a pregnant animal, it is important to consider that the physiological changes during pregnancy can affect how the drug is absorbed, distributed, and eliminated from the body. It is also essential to evaluate whether the drug can reach the fetus. When initiating antimicrobial therapy, it is important to ensure that effective concentrations of the antimicrobial are achieved in the body in order to guarantee the efficacy. The main objective of this study was to model the pharmacokinetics of enrofloxacin and its active metabolite, ciprofloxacin, using mathematical–statistical models (called nonlinear mixed-effects models) and subsequent pharmacokinetic simulation. The results of this study show that both drugs crossed the placenta and reached the fetus, with higher concentrations of enrofloxacin than ciprofloxacin, and conclude that an enrofloxacin dose regimen of 10 mg/kg/day was the most appropriate for the treatment of infections by susceptible microorganisms in pregnant goats. It is important to emphasize that a correct dosage is vital to maximize the effectiveness of the treatment, minimizing the risk of adverse effects in the animals and the emergence of antimicrobial resistance.

The pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin, as well as the placental transfer of enrofloxacin and ciprofloxacin, have not been studied. The aims of this study were (1) to evaluate the pharmacokinetics of enrofloxacin and ciprofloxacin by intravenous and intramuscular administration of 7.5 mg/kg in pregnant goats; (2) to determine the placental transfer of enrofloxacin and ciprofloxacin; (3) to conduct a PK/PD analysis to calculate the PK/PD cutoff of different dose regimens; and (4) to evaluate the tentative epidemiological cutoff values for coagulase-negative staphylococci wild-type isolates from goats. Plasmatic concentrations of enrofloxacin and ciprofloxacin in pregnant goats were well described by the parent–metabolite model. Simultaneous modeling of enrofloxacin and ciprofloxacin in each individual allowed for a PK/PD analysis that considered both drugs with antimicrobial activity. Our results show that both enrofloxacin and ciprofloxacin crossed the placenta in goats: fetal/maternal concentration ratio were 0.58 ± 0.05 and 0.03 ± 0.01 for enrofloxacin and ciprofloxacin. MIC values of coagulase-negative staphylococci isolates (n = 90) were obtained, and tentative epidemiological cutoffs were calculated at 0.25 and 0.5 mg/L for enrofloxacin and ciprofloxacin. According to PK/PDco values, an intravenous dose regimen of 10 mg/kg/day was considered the most appropriate, but based on the PK/PDco, culture, and AST data, an effective dosing regimen with the lowest possible dose could be selected to minimize the potential risk of fetal exposure to enrofloxacin.