{"title":"Physiologically-Based Modeling of Methylprednisolone Pharmacokinetics Across Species with Extrapolations to Humans.","authors":"Ruihong Yu, William J Jusko","doi":"10.1016/j.xphs.2025.103719","DOIUrl":null,"url":null,"abstract":"<p><p>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<sub>d</sub>) from noncompartmental analysis highly correlated with body weights (R<sup>2</sup> > 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.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"103719"},"PeriodicalIF":3.7000,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of pharmaceutical sciences","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.xphs.2025.103719","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
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 (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.
期刊介绍:
The Journal of Pharmaceutical Sciences will publish original research papers, original research notes, invited topical reviews (including Minireviews), and editorial commentary and news. The area of focus shall be concepts in basic pharmaceutical science and such topics as chemical processing of pharmaceuticals, including crystallization, lyophilization, chemical stability of drugs, pharmacokinetics, biopharmaceutics, pharmacodynamics, pro-drug developments, metabolic disposition of bioactive agents, dosage form design, protein-peptide chemistry and biotechnology specifically as these relate to pharmaceutical technology, and targeted drug delivery.