ORIGINAL ARTICLE
Meta-Analysis and Mechanism-Based Modeling of Synovial and Plasma Pharmacokinetics and Adrenal Suppression Following Intra-Articular Injection of Methylprednisolone Acetate in Horses
Ruihong Yu,
William J. Jusko,
Ruihong Yu
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, New York, USA
Search for more papers by this authorCorresponding Author
William J. Jusko
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, New York, USA
Correspondence:
William J. Jusko ([email protected])
Search for more papers by this authorRuihong Yu,
William J. Jusko,
Ruihong Yu
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, New York, USA
Search for more papers by this authorCorresponding Author
William J. Jusko
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, New York, USA
Correspondence:
William J. Jusko ([email protected])
Search for more papers by this authorFunding: This work was supported by the National Institute of General Medical Sciences, NIH (R35 GM131800).
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.
Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
The authors declare that all the data utilized in this study are available in the figures in this article. Further datasets digitized and/or analyzed during the study are available from the corresponding author upon reasonable request.
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