Meta-analysis of levamisole absorption and disposition across diverse species using a minimal physiologically-based pharmacokinetic model

Purpose: Pharmacokinetic (PK) data for levamisole, an important immunostimulant and antiparasitic agent, were identified in 18 species providing sufficient PK data following oral (PO) and/or intravenous (IV) administration for assessment and comparison. Methods: Pharmacokinetic parameters were sought in all species for traditional allometric assessment. Among these, 2 bird and 6 mammalian species provided sufficient data for joint modeling using traditional compartmental PK and minimal physiologically-based pharmacokinetic (mPBPK) methods. Results: Simple allometric scaling was first used examine clearance (CL), steady-state volume of distribution (V_ss), absorption rate constant (k_a), and bioavailability (F) in relation to body weight (BW) across species. The V_ss correlated well with BW (Parameter = α·BW^b) with b = 0.89 (R² = 0.81) whereas CL (b = 0.26, R² = 0.46), k_a (b = 0.25, R² = 0.14), and F (b = 0.08, R² = 0.70) showed weaker correlations with ducks appearing as outliers for CL. Biexponential PK profiles were adequately captured using an allometric two-compartment model (2CM). Joint fitting of IV PK data from 8 species to a generalized mPBPK model, incorporating unified distribution parameters (e.g., tissue partition coefficient K_p and fractional distribution parameter f_d), yielded good performance across species. The mPBPK model assuming high tissue permeability and species-specific K_p values for pig and chicken (K_{p, pig} and K_{p, chicken}) best described the observed profiles. Oral bioavailability(F) was highly consistent across all species (50–80%), with the exception of goats. Conclusion: This study demonstrates that levamisole with rapid absorption and extensive metabolism exhibits largely consistent PK properties across species. Minimal PBPK modeling offers advantageous comparison of interspecies determinants of levamisole PK.