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Purpose <p>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.</p> Methods <p>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.</p> Results <p>Simple allometric scaling was first used examine clearance (<i>CL</i>), steady-state volume of distribution (<i>V</i><sub><i>ss</i></sub>), absorption rate constant (<i>k</i><sub><i>a</i></sub>), and bioavailability (<i>F</i>) in relation to body weight (<i>BW</i>) across species. The <i>V</i><sub><i>ss</i></sub> correlated well with <i>BW (Parameter = α·BW</i><sup><i>b</i></sup><i>)</i> with <i>b</i> = 0.89 (R<sup>2</sup> = 0.81) whereas <i>CL</i> (<i>b</i> = 0.26, R<sup>2</sup> = 0.46), <i>k</i><sub><i>a</i></sub> (<i>b</i> = 0.25, R<sup>2</sup> = 0.14), and <i>F</i> (<i>b</i> = 0.08, R<sup>2</sup> = 0.70) showed weaker correlations with ducks appearing as outliers for <i>CL</i>. 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 <i>K</i><sub><i>p</i></sub> and fractional distribution parameter <i>f</i><sub><i>d</i></sub>), yielded good performance across species. The mPBPK model assuming high tissue permeability and species-specific <i>K</i><sub><i>p</i></sub> values for pig and chicken (<i>K</i><sub><i>p, pig</i></sub> and <i>K</i><sub><i>p, chicken</i></sub>) best described the observed profiles. Oral bioavailability(<i>F</i>) was highly consistent across all species (50–80%), with the exception of goats.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月11日

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  • ChunFu Cheng,
  • Yoo-Seong Jeong,
  • William J. Jusko

摘要

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 (Vss), absorption rate constant (ka), and bioavailability (F) in relation to body weight (BW) across species. The Vss correlated well with BW (Parameter = α·BWb) with b = 0.89 (R2 = 0.81) whereas CL (b = 0.26, R2 = 0.46), ka (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 Kp and fractional distribution parameter fd), yielded good performance across species. The mPBPK model assuming high tissue permeability and species-specific Kp values for pig and chicken (Kp, pig and Kp, 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.