(M-130) Across-species meta-analysis of methylprednisolone reversible metabolism and pharmacokinetics utilizing allometric and scaling model approaches

William Jusko, PhD – Distinguished professor, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA

Objectives: Methylprednisolone (MPL) is a frequently and chronically used corticosteroid in animals and humans for treatment of inflammatory and autoimmune diseases. The reversible conversion with its metabolite, methylprednisone (MPN), has been well recognized and quantitatively assessed in rats utilizing a dual physiologically based pharmacokinetic (PBPK) model with multiple complexities [1]. This study seeks to allometrically assess literature datasets across species and to predict clinical pharmacokinetics of MPL.

Methods: The plasma profiles and pharmacokinetic (PK) parameters of MPL in seven species were collected and digitized from the literature. The systemic clearances (CL) and distribution volume (Vd) of MPL were assessed by a simple allometric correlation with animal body weights (BW). Using the physiological and anatomical variables for each specie, a dual minimal PBPK model of MPL/MPN consisting of blood, liver & kidney, and remainder tissue compartments and incorporating saturable tissue binding and multi-site reversible/irreversible drug conversions was applied to jointly fit overall plasma concentration-time datasets and estimate allometric parameters. According to the allometric relationships, human plasma and various tissue concentration profiles for a recommended dose regimen (2 mg/kg/day, 7 days, IV) [2] for COVID-19 treatment were simulated through scaling up our recent rat-sourced whole-body PBPK model of MPL/MPN [1].

Results: The reported CL and Vd of MPL in rat, guinea pig, cat, rabbit, dog, human, and horse highly correlate with BW (R2 = 0.81 and 0.95). The proposed minimal PBPK model adequately captured profiles from all species if an assigned adjustment factor was used for elimination clearance of MPL (CLL0) and MPN (CLN0) in rats (estimated as 5.52). The MPL→MPN conversion clearance (CLLN), back conversion clearance (CLNL), CLL0, and CLN0 occurring in the lumped liver & kidney compartment were well depicted as CL (mL/h) = a·BW(kg)b with scaling intercepts (a) of 0.12, 2.46, 0.55, 0.69 and shared exponent (b) of 0.97. The conversion of MPL→MPN in the remainder compartment employed a Michaelis-Menten process with Vmax (ng/h) as 5780·BW(kg)0.66 and Km as 1319 ng/mL. Saturable tissue binding of MPL existed in the two tissue compartments and that of MPN in the liver & kidney and all tissue partition parameter estimates were comparable to reported values from the whole body model. The simulated MPL PK presented exquisite concentration profiles of tissues in humans. A trough steady-state concentration of 58.5 ng/mL (156 nM) was achieved in lung, which is comparable to the published IC50 (143 nM) of MPL inhibition of human lymphocyte proliferation [3].

Conclusions: The minimal PBPK model is suitable for allometric scaling and fitting of the PK of MPL in different species. Together with our whole-body PBPK model [1], it provides further insights into complexities of MPL exposure and actions in various tissues.

Citations: [1] Yu R and Jusko WJ (2024) Physiologically based pharmacokinetic modeling the reversible metabolism and tissue-specific partitioning of methylprednisolone and methylprednisone in rats. Drug Metab Dispos: Accepted.
[2] Azemi NFN, Islahudin F, Khan RA. et al (2024) Methylprednisolone use in hospitalized COVID-19 patients: a retrospective study. J Pharm Policy Pract 17: 2337125.
[3] Cuzzoni E, De Iudicibus S, Bartoli F, et al (2012). Association between BclI polymorphism in the NR3C1 gene and in vitro individual variations in lymphocyte responses to methylprednisolone. Br J Clin Pharmacol 73:651-655.