Physiologically-Based Modeling of Methylprednisolone Pharmacokinetics Across Species with Extrapolations to Humans.

Abstract

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 (V_d) 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.