Gradudate Student University at Buffalo, United States
Objectives: The study aims to (1) perform a literature search and meta-analysis to recover pharmacokinetic (PK) parameters of levamisole (LVM) across various species, (2) evaluate potential relationships among these PK parameters using allometric two-compartment model (a2CM), and (3) employ a minimal physiological-based pharmacokinetic (mPBPK) model to analyze the plasma concentration time-course of LVM across eight species.
Methods: Data were collected from PubMed and Google Scholar, spanning publications from 1930 to 2024. PK parameters were gathered for 19 species, with eight species selected for detailed analysis. PK parameters were assessed using non-compartmental analysis (NCA) and allometric scaling. A two-compartment model (2CM) was used for initial PK profiling. An mPBPK model was developed to fit the plasma concentration-time data, incorporating physiological parameters like blood volume, cardiac output, and body weight across species. Both models were fitted to IV and oral (PO) data using maximum likelihood methods.
Results: The study found that the clearance (CL) of LVM across species showed a low power coefficient (b=0.26) when scaled allometrically, indicating unique PK properties. The volume of distribution (Vss) demonstrated a strong correlation with body weight (b=0.89). The absorption rate constant (ka) had a poor allometric relationship (b=0.25), while bioavailability (F) was consistent across species (b=0.08). Joint fitting of the a2CM and mPBPK models provided similar results, with the mPBPK model showing better fit and lower coefficients of variation (CV%). The mPBPK model with a unified tissue partition coefficient (Kp) and pig-specific Kp parameter provided the most accurate fits. The study highlighted the consistency in bioavailability (50-100%) across species, with exceptions such as the goat.
Conclusion: Levamisole exhibits consistent allometric properties across multiple species, characterized by a low clearance power coefficient and proportional volume of distribution to body weight. The mPBPK model demonstrated better overall fitting compared to the a2CM model, capturing species-specific PK profiles effectively. This study underscores the value of allometric scaling and mPBPK modeling in cross-species PK assessments, providing insights into levamisole's disposition in diverse biological systems.
Citations: [1] Song, D., & Jusko, W. J. (2021). Across-species meta-analysis of dexamethasone pharmacokinetics utilizing allometric and scaling modeling approaches. Biopharmaceutics & drug disposition, 42(5), 191–203. [2] Jeong, Y. S., & Jusko, W. J. (2021). Meta-Assessment of Metformin Absorption and Disposition Pharmacokinetics in Nine Species. Pharmaceuticals (Basel, Switzerland), 14(6), 545.
