Lien Ngo (1), Jaeseong Oh (2), Thi Quyen Tran (1), Woo Jin Jung (1), Seon Jong Park (1), Chung Hee Lee (1), Sung Yoon Yang (1), Jung-woo Chae (1), Howard Lee (2,3), Hwi-Yeol Yun (1)
(1) College of Pharmacy, Chungnam National University, South of Korea, (2) Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital and College of Medicine, South of Korea, (3) Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, South of Korea
Introductions: Anakinra (Kineret; Amgen) is approved for the treatment of Rheumatoid arthritis (RA) (2001), cryopyrin-associated periodic syndromes (CAPS) (2012), and Still’s disease (2018) [1], [2]. HL2351 (hIL-1Ra-hyFc) is a recombinant protein formed by the fusion of two human IL1Ra components (the active ingredient of Anakinra) into one antibody-derived fragment crystallizable (Fc) portion. While HL2351 has the same pharmacological mechanism of action as Anakinra, its long half-life is expected to relieve the discomfort of using Anakinra due to the once-daily dosing method and to provide improved therapeutic efficacy.
Objectives: In this study, we aimed to develop a population pharmacokinetic (PopPKs) model for HL2351 in humans with the characterization of the target-mediated drug disposition (TMDD) and neonatal Fc receptor (FcRn) mediated recycling process using NONMEM software. Accordingly, dose regimens for HL2351 that imitate the therapeutic actions of Anakinra for the treatment of RA, CAPS, and Still’s disease were suggested.
Methods: Pharmacokinetic (PK) data were collected from a Phase 1 study. In which, HL2351 (1, 2, 4, 8, or 12 mg/kg doses) or Anakinra (100 mg/kg dose) were subcutaneously injected into healthy subjects (six groups, n=8/group). A two-compartmental disposition model was applied for both HL2351 and Anakinra. A quasi-steady-state (QSS) approximation to characterize the interactions of HL2351 with its receptors, including IL1R (TMDD, binding via the IL1Ra portion) [3] and FcRn (FcRn-mediated recycling process, binding via the IgG4-sourced Fc portion) [4], [5] was developed. A QSS TMDD approximation model was also developed to characterize the interaction of Anakinra with IL1R. PopPK analysis was conducted using NONMEM executed through PsN software tool using Pirana [6]. The final model was selected by comparing objective function value using the likelihood ratio test within NONMEM at 5% significant level, goodness-of-fit plots, and precision of estimates, and was evaluated based on graphical analysis and statistical methods. The developed PopPK models were applied to simulate PK profiles of HL2351 (1, 2, 4, 8, or 12 mg/kg, once 2-weekly) and Anakinra (100 mg/day or 1, 2, 3, 4, or 8 mg/kg/day, once-daily) in healthy humans. The average plasma concentration at the steady-state (Css) of each drug at each dose was calculated, which was then used as a criterion for doses suggestion. It was assumed that to HL2351 mimic the therapeutic effects of Anakinra, Css of HL2351 need to reaches Css of Anakinra at respective recommended Anakinra dose.
Results: An integrated TMDD and FcRn-mediated recycling PopPK model was successfully developed and evaluated to describe the PKs of HL2351. By the model, QSS constants for the binding of HL2351 with IL1R were estimated to be 14.8 nM. The total active amount of FcRn at the distribution space was 750 nmol. The total active concentration of IL1R for binding with HL2351 was 2.23 nM. In addition, a TMDD model was successfully developed and evaluated to describe the PKs of Anakinra. The simulated Css of HL2351 following the injection of HL2351 at the doses of 1, 2, 4, 8, or 12 mg/kg, once 2-weekly, was 3.70, 7.70, 15.70, 30.45, 43.96 nM, respectively. The relationship between Css and the administered HL2351 dose was described by a linear regression equation with a corresponding coefficient of determination (R^2) as Css = 4.2928×Dose – 1.1632 (R^2=0.9886). The simulated Css of Anakinra following the injection of Anakinra at the doses of 100 mg/day, or 1, 2, 3, 4, or 8 mg/kg/day, once-daily, was 26.0, or 18.0, 36.7, 55.4, 74.1, or 148.9 nM, respectively. Accordingly, to mimic the effects of Anakinra following the dose of 100 mg/day, or 1, 2, 3, 4, or 8 mg/kg/day, once-daily, the HL2351 doses were estimated to be 7.00, or 4.50, 9.50, 15.0, 20.0, or 40.5 mg/kg/once 2-weekly, respectively.
Conclusions: An integrated TMDD and FcRn-mediated recycling model and a TMDD model have been developed successfully to describe PKs of HL2351 and Anakinra, respectively, following a single subcutaneous injection of drugs in healthy humans. By applying the developed PopPK models, to mimic the effects of Anakinra following the dose of 100 mg/day, or 1, 2, 3, 4, or 8 mg/kg/day, once-daily, the suggestion dose for HL2351 when the drug was desired to be administered once 2-weekly was 7.00, or 4.50, 9.50, 15.0, 20.0, or 40.5 mg/kg/once 2-weekly, respectively.
References:
[1] European Medicines Agency, “Kineret: EPAR – Product Information,” 2019.
[2] U.S. Food and Drug Administration, “Kineret® (anakinra) for injection, for subcutaneous use,” 2012.
[3] P. Ma, “Theoretical Considerations of Target-Mediated Drug Disposition Models: Simplifications and Approximations,” Pharm. Res., vol. 29, no. 3, pp. 866–882, Mar. 2012.
[4] R. P. Junghans and C. L. Anderson, “The protection receptor for IgG catabolism is the beta2-microglobulin-containing neonatal intestinal transport receptor.,” Proc. Natl. Acad. Sci., vol. 93, no. 11, pp. 5512–5516, May 1996.
[5] F. W. R. BRAMBELL, W. A. HEMMINGS, and I. G. MORRIS, “A Theoretical Model of γ-Globulin Catabolism,” Nature, vol. 203, no. 4952, pp. 1352–1355, Sep. 1964.
[6] R. J. Keizer, M. O. Karlsson, and A. Hooker, “Modeling and Simulation Workbench for NONMEM: Tutorial on Pirana, PsN, and Xpose.,” CPT pharmacometrics Syst. Pharmacol., vol. 2, p. e50, Jun. 2013
Reference: PAGE () Abstr 9428 [www.page-meeting.org/?abstract=9428]
Poster: Drug/Disease Modelling - Other Topics