Exploratory Pharmacokinetic Characterization of Enrofloxacin and Ciprofloxacin in Plasma and Interstitial Fluid of Dogs: Nonlinear Mixed-Effects Modeling and PK/PD Target Attainment Analysis.

BACKGROUND

Assessment of antimicrobial exposure at the site of infection is essential for pharmacokinetic/pharmacodynamic (PK/PD)-guided antimicrobial therapy, yet plasma concentrations may not adequately reflect extracellular target-site exposure. This study characterized the pharmacokinetics of enrofloxacin and its active metabolite ciprofloxacin in plasma and interstitial fluid (ISF) following high-dose oral enrofloxacin administration in dogs and evaluated PK/PD target attainment using nonlinear mixed-effects (NLME) modeling and Monte Carlo simulation.

METHODS

Nine healthy Beagle dogs were enrolled and received a single oral dose of enrofloxacin (target dose 20 mg/kg). Following exclusion of one dog after vomiting, pharmacokinetic analyses included plasma data from eight dogs and interstitial fluid (ISF) data from six dogs. Serial plasma samples and protein-free ISF samples collected over 24 h by in vivo ultrafiltration were analyzed using LC-MS/MS. Non-compartmental and population pharmacokinetic analyses were performed separately for plasma and ISF data. Final population models were used to simulate 5000 virtual individuals for probability of target attainment (PTA) analyses across a range of minimum inhibitory concentrations (MICs) using established AUC0-24/MIC and Cmax/MIC targets.

RESULTS

Both enrofloxacin and ciprofloxacin exhibited delayed peak concentrations and greater overall exposure in ISF than in plasma. For enrofloxacin, mean AUC0-24 was higher in ISF than in plasma (44.9 vs. 21.6 µg × h/mL). Exploratory population pharmacokinetic models adequately described the plasma and ISF concentration-time data. Monte Carlo simulations showed consistently higher PTA in ISF than in plasma. For the more conservative AUC0-24/MIC targets (≥100 and ≥125), the MIC associated with ≥90% PTA for enrofloxacin was four-fold higher in ISF than in plasma (0.125 vs. 0.03 µg/mL).

CONCLUSIONS

High-dose oral enrofloxacin produced sustained extracellular exposure, resulting in more favorable PK/PD target attainment in ISF than in plasma. These findings indicate that plasma pharmacokinetics alone may not accurately reflect target-site antimicrobial exposure and support further evaluation of ISF-based pharmacokinetic data for PK/PD-guided optimization of fluoroquinolone therapy in dogs.