Physiologically-based modeling of methylprednisolone pharmacokinetics across species with extrapolations to humans

• Published in: Journal of pharmaceutical sciences Vol. 114; no. 5; p. 103719
• Main Authors: Yu, Ruihong, Jusko, William J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2025
• Subjects: Animals; Anti-Inflammatory Agents - blood; Anti-Inflammatory Agents - pharmacokinetics; Clearance; Human extrapolation; Humans; Methylprednisolone; Methylprednisolone - blood; Methylprednisolone - pharmacokinetics; Models, Biological; Pharmacokinetics; Rats; Species scaling; Species Specificity; Tissue Distribution; Species scaling; Clearance; Methylprednisolone; Pharmacokinetics; Human extrapolation
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1016/j.xphs.2025.103719

•This study characterized and parameterized the allometric scaling relationships of methylprednisolone (MPL) pharmacokinetics (PK) across seven species, revealing an allometric exponent of approximately 1.0 for clearances.•A series of physiologically based pharmacokinetic (PBPK) –basic, intermediate, and full versions– was developed to analyze and simulate MPL PK, catering to diverse practical needs in both clinical and veterinary contexts.•These models showed a conservation of tissue distribution properties of MPL across species while demonstrating partial allometric scaling and further adjustments of elimination mechanisms when applied to humans.•The whole-body PBPK model, translated from rats to humans, demonstrated excellent application performances for plasma PK profiles in healthy subjects and patients and is capable of simulating tissue kinetics under various MPL dosing regimens. Methylprednisolone (MPL) is widely used in clinical and veterinary medicine to manage inflammation. Plasma profiles and PK parameters in 7 species were digitized from 10 literature sources along with our recent PBPK results in rats. Basic allometric scaling provided reported clearance (CL) and distribution volume (Vd) from noncompartmental analysis highly correlated with body weights (R2 > 0.96), although rat CL deviated from the linear trend. A basic nonlinear minimal physiologically-based pharmacokinetic model (mPBPK) (Model I), an intermediate reversible-metabolism mPBPK model (Model II) accounting for MPL and methylprednisone interconversion, and a full highly complex PBPK model were used to assess the interspecies plasma concentration datasets. The MPL PK profiles were reasonably captured by Model I and II, yielding allometric exponents for CL of 1.15 and 0.94, consistent with basic allometry, 1.18. Rat PK informed the presence of nonlinear tissue binding and required an adjustment factor approximately 8-fold higher for its CL. Our full PBPK model was extrapolated from rats to humans using allometry from Model II and optimized producing excellent applications in healthy subjects and patients. This study, based on conserved tissue binding properties, provided three allometric translational PBPK models for MPL, facilitating reasonable PK assessment and interpretation for various species.