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

作者：ChunFu Cheng, Yoo‐Seong Jeong, William J. Jusko · 发表于：Journal of Pharmaceutical Investigation · 年份：2025 · DOI：10.1007/s40005-025-00770-6 · 被引用次数：3 · 研究领域：Helminth infection and control、Coccidia and coccidiosis research、Animal testing and alternatives

Abstract 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 (R 2 = 0.81) whereas CL ( b = 0.26, R 2 = 0.46), k a ( b = 0.25, R 2 = 0.14), and F ( b = 0.08, R 2 = 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, chi...