Meta-Analysis of the Input and Disposition of Various Dosage Forms of Methylprednisolone in Healthy Subjects Utilizing a Physiologically Based Pharmacokinetic Model

• Published in: The AAPS journal Vol. 27; no. 1; p. 24
• Main Authors: Yu, Ruihong, Jusko, William J.
• Format: Journal Article
• Language: English
• Published: United States Springer 09.01.2025
• Subjects: Administration, Oral; Analysis; Biological Availability; Corticosteroids; Esters; Generic drugs; Half-Life; Healthy Volunteers; Humans; Injections, Intramuscular; Liver; Methylprednisolone; Methylprednisolone - administration & dosage; Methylprednisolone - pharmacokinetics; Models, Biological; Phosphates; Tissue Distribution; methylprednisolone; pharmacokinetics; prodrug conversion; minimal physiologically based pharmacokinetic model (mPBPK model); human
• ISSN: 1550-7416; 1550-7416
• DOI: 10.1208/s12248-024-01011-8

The study quantitatively analyzes and compares the pharmacokinetics (PK) of methylprednisolone (MPL) in humans upon administration of various dosage forms. The PK parameters and profiles of MPL in healthy subjects were collected from 22 literature sources. A minimal physiologically based pharmacokinetic (mPBPK) model consisting of blood and two tissue (lumped liver and kidney, remainder) compartments with nonlinear tissue partitioning was applied to describe MPL disposition. Overall 18 plasma concentration profiles were well captured and 85% of PK parameters reasonably estimated. The clearance (CL) of MPL averaged 336 mL/h/kg and appeared slightly nonlinear across a dosage range of 5 to 800 mg, the distribution volume (V ) averaged 1.17 L/kg, and the model predicted elimination half-life (t ) was 2.6 h. Rapid prodrug conversion was found for intravenous MPL sodium succinate (MPSS) with a t of 1.7 min, and followed by MPL phosphate (MPPS) 3.8 min, MPL hemisuccinate (MPHS) 16 min, and MPL suleptanate (MPSP) 2.9 h. Their bioavailabilities (F) varied slightly from 60 to 73%. Intramuscular doses showed an absorption rate constant (k ) of 1.5 h for MPSS and 96 h for MPSP. Oral doses of 5 formulations were examined. Medrol exhibited greatest absorption with F of 74% and k of 2.1 h , while one generic product had F of 32.6%. This study demonstrated the utility of a mechanistic mPBPK disposition model for comparing MPL formation from various esters, absorption from several oral dose formulations, and modest variability across numerous PK studies in healthy humans.