Meta-Analysis and Mechanism-Based Modeling of Synovial and Plasma Pharmacokinetics and Adrenal Suppression Following Intra-Articular Injection of Methylprednisolone Acetate in Horses.

Abstract

This study assesses the pharmacokinetics (PK) of published methylprednisolone (MPL) data in horses following intra-articular (IA) administration of MPL acetate (MPA) and the associated adrenal suppression. The concentrations of MPL/MPA in synovial fluid, blood, and urine, as well as hydrocortisone (HC) in plasma, were digitized from multiple sources in the literature. A minimal physiologically based pharmacokinetic model and a linked indirect response model with a circadian rhythm baseline were applied. Concentrations of MPA in joints followed a triexponential decay, converting to MPL. The clearance of MPL was 797 mL/h/kg via hepatic metabolism (93%) and renal excretion (7%). The persistence of MPL in synovium and plasma for over 500 h was primarily ascribed to slow prodrug dissolution. The formation of MPL from available MPA in SF was rapid. A transit step was needed between the synovium and plasma for MPL absorption. The MPA to MPL bioavailability was dose and/or study dependent; 100% for dosages below 100 mg and 58% for 200 mg. The MPL inhibition of HC production was potent, with an IC₅₀ of 0.83 ng/mL, and lasted over 50 h. This meta-analysis utilizing a mechanistic modeling approach provided advanced and comprehensive insights on IA MPL PK in horses and was translatable for the PK appreciation of IA MPA dosing in man.