Metronidazole Pharmacokinetics Across Species: Meta-Analysis Integrating Allometric Scaling and Minimal Physiologically-Based Pharmacokinetic Modeling

Metronidazole (MTZ) is frequently used in both human and veterinary medicine to treat infections caused by certain protozoa and anaerobic bacteria. This study investigates the pharmacokinetic (PK) profiles of MTZ for available species in the literature by utilizing a linear, allometric, minimal physiologically-based PK (mPBPK) model. High quality PK data for intravenous (IV, n = 13) and oral (PO, n = 10) single doses were collected. Reported clearances (CL) and volumes of distribution (V_SS) were highly correlated (R² = 0.957, 0.969) with body weights (BW) with allometric power coefficients of 0.97 and 0.87. A mPBPK model with one perfusion-limited tissue compartment was used to evaluate MTZ PK using anatomical and physiological parameters for each species. The mPBPK model adequately captured the IV PK profiles when using species-specific CL values and a generalized tissue:plasma partition coefficient (K_p = 0.792 (CV 2.76%)) except for sheep and goats that had very low K_p values. The IV and PO profiles were best fitted jointly with shared physiological parameters and species-specific clearances, K_p values (range 0.55 to 1.44, mean 0.86), and bioavailability (F 0.32 – 1.00, mean 0.73). Overall, successfully integrating allometric scaling into a mPBPK model for diverse species revealed very consistent disposition of MTZ with generally BW-proportional CL values, reasonably conserved K_p values, and a moderate range of absorption rates and high bioavailability.