Evaluating Orally Administered Meloxicam-Loaded Polymeric Nanocapsules in Female Dogs: A Population Pharmacokinetic Modeling Study

<b>Background/Objectives</b>: Meloxicam (MLX) is a nonsteroidal anti-inflammatory drug (NSAID) recommended for treating acute and chronic pain in dogs, frequently administered prophylactically to mitigate postoperative pain; however, its utility is limited by characteristic NSAID-associated adverse effects, such as gastrointestinal side effects. Nanosystems offer the potential to minimize adverse effects by sustaining drug release. Therefore, this study assessed the pharmacokinetics of MLX nanoencapsulation in female dogs undergoing ovariohysterectomy using a population pharmacokinetic (PopPK) modeling approach. <b>Methods</b>: MLX-loaded polymeric nanocapsules (NC-MLX) were prepared using the nanoprecipitation method and characterized by zeta potential, pH, mean diameter, particle size distribution, and drug content. Dogs received 0.2 mg/kg of either NC-MLX or free MLX orally, 4 h before surgery, and plasma samples were analyzed using an HPLC-PDA method. Pharmacokinetics were characterized by non-compartmental analysis and PopPK modeling. Several compartmental structures, variability models, and residual error models were explored, and relevant covariates were investigated. <b>Results:</b> NC-MLX had an average diameter of 326 ± 13 nm, a zeta potential of -26.2 ± 6.4 mV, and drug loading of 99.47% ± 0.01%. NC-MLX showed a significant increase in the t_1/2 (36.99 ± 17.26 h) of MLX compared to the free drug (15.22 ± 4.4 h). The best-fitting PopPK model was a two-compartment model with double extravascular first-order absorption rate constants (Ka₁ and Ka₂), including a lag time for Ka₂ and linear elimination, describing the second peak observed in several animals. The nanoformulation was a significant covariate for Tlag₂, delaying the time for absorption (1.22 and 2.55 h for free MLX and NC-MLX, respectively) and increasing V₂ (0.134 and 0.402 L/kg for free MLX and NC-MLX, respectively). External model validation showed that the final PopPK model accurately predicted plasma concentrations, with MPE% and RMSE values below 15%. <b>Conclusions</b>: Our findings suggest that NC-MLX alters MLX absorption and distribution profiles, supporting its potential as an alternative for postoperative pain management in dogs.