Physiology-Based Pharmacokinetic Modeling for Prediction of Gentamicin Plasma Profile in Dogs with Renal Dysfunction

Background/Objectives: The aim of the study was to develop a physiologically based pharmacokinetic (PBPK) model to predict gentamicin therapeutic protocols for dogs with varying degrees of renal function impairment, considering the minimum inhibitory concentrations (MICs) of the infecting bacteria. Methods: The PBPK model was built using PK-Sim^® software (OPEN SYSTEMS PHARMACOLOGY), based on pharmacokinetic data available in the literature and information on the physicochemical properties of the drug. Model evaluation included the calculation of the geometric mean fold error (GMFE), weighted and percentage residuals were calculated, as well as the following measures: AFE, AWRi, MWRi, MAWRi, APE%, MPE%, MAPE%, MdPE%, and MdAPE%. Therapeutic efficacy was assessed according to the Probability of Target Attainment (PTA), considering an MIC distribution of 0.25 to 8 μg/mL for different doses (2, 4, 6, 8, and 10 mg/kg) using the PK/PD indices C_max/MIC ≥ 10, AUC/MIC ≥ 50, and AUC/MIC ≥ 110. To compare the pharmacokinetics of gentamicin between healthy dogs and those with decreased renal function, different GFR values corresponding to stages of renal impairment were used, as determined by clinical biomarkers (microalbuminuria, UPC ≥ 2, sCr ≥ 1.2 mg/dL, sCr ≥ 2.4 mg/dL, and sCr ≥ 5 mg/dL). The risk of toxicity was assessed according to AUC_24h ≥ 700 mg·h/L and C_min ≥ 0.5. Results: The model demonstrated good predictive performance, with a GMFE value of 1.13 meeting the double error criterion, and weighted residuals randomly distributed around 0 (p = 0.3792). Through the calculation of PTA, it was observed that efficacy varied according to the PK/PD index used, but values greater than 90% were obtained for MICs up to 4 μg/mL. The model allowed the estimation of protocols for each stage of renal impairment, considering the GFR of each group and the risk of nephrotoxicity, in association with the optimal dose to ensure therapeutic efficacy. Conclusions: These findings make it possible to propose a dose for the treatment of an infection, considering the MIC and the patient's GFR stage, thereby reducing the risk of adverse effects without compromising treatment efficacy.