Population pharmacokinetic analysis of peficitinib in patients with rheumatoid arthritis

Junko Toyoshima, Mai Shibata, Atsunori Kaibara, Yuichiro Kaneko, Hiroyuki Izutsu, Tetsuya Nishimura, Junko Toyoshima, Mai Shibata, Atsunori Kaibara, Yuichiro Kaneko, Hiroyuki Izutsu, Tetsuya Nishimura

Abstract

Aims: To analyse the population pharmacokinetics (PK) of peficitinib in patients with rheumatoid arthritis (RA) and assess the potential PK covariates to identify the requirement for dose adjustment in RA patients.

Methods: The analysis incorporated 2464 observations from 98 healthy volunteers and 4919 observations from 989 RA patients. A population PK model for peficitinib in RA patients was constructed by a nonlinear mixed effect model using NONMEM with prior information from a healthy volunteer model.

Results: A 2-compartment model with sequential zero- and first-order absorption and lag time was constructed for RA patients. Covariate exploration in the RA patient model revealed that estimated glomerular filtration rate (eGFR) and lymphocyte count had a significant effect on apparent total systemic clearance (CL), which was 91.7 L/h (2.3% relative standard error). Compared with the mean population CL, the model predicted mean changes in CL of 12.3 and -10.7% in patients with observed minimum and maximum lymphocyte count of 500 and 4600 106 /L, respectively, and mean changes in CL of -17.8 and 16.7% in patients with minimum and maximum eGFR of 36.4 and 188 mL/min/1.73m2 , respectively. The simulated population mean area under plasma concentration-time curve for 24 hours after dosing showed a 1.35-fold increase in patients with severe renal impairment (eGFR 22.5 mL/min/1.73m2 ) compared with patients with reference eGFR (91.5 mL/min/1.73m2 ).

Conclusion: The population PK model identified eGFR and lymphocyte count as covariates for CL. The magnitude of changes was not considered clinically relevant, indicating no requirement for dose adjustment.

Trial registration: ClinicalTrials.gov NCT02586194 NCT02603497 NCT02760342 NCT02531191 NCT02308163 NCT02305849 NCT01565655.

Keywords: pharmacokinetics; population analysis; rheumatoid arthritis.

Conflict of interest statement

J. Toyoshima, M. Shibata, Y. Kaneko, H. Izutsu and T. Nishimura are full‐time employees of Astellas Pharma Inc., Tokyo, Japan. A. Kaibara was a full‐time employee of Astellas Pharma Inc., Tokyo, Japan, at the time of analysis. He is currently a full‐time employee of Eli Lilly Japan K.K., Tokyo, Japan.

© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

FIGURE 1
FIGURE 1
Goodness‐of‐fit plots for the rheumatoid arthritis patient model. |iWRES|, absolute values of individual weighted residuals; CWRES, conditional weighted residuals; red lines, LOWESS smoothing curves; blue circles, observations
FIGURE 2
FIGURE 2
Prediction‐corrected visual predictive check of the rheumatoid arthritis patient model. Black circles, observations in healthy volunteers; red solid curve and red dashed curves, the median, 2.5th percentile and 97.5th percentile of observations; pink and grey areas, 95% confidence intervals of the median, 2.5th percentile and 97.5th percentile of simulated data; black dashed line, lower limit of quantitation (0.2500 ng/mL)

References

    1. O'Dell JR. Therapeutic strategies for rheumatoid arthritis. Wood AJJ, editor. N Engl J Med. 2004;350(25):2591‐2602.
    1. Smolen JS, Breedveld FC, Burmester GR, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis. 2016;75(1):3‐15.
    1. Zampeli E, Vlachoyiannopoulos PG, Tzioufas AG. Treatment of rheumatoid arthritis: unraveling the conundrum. J Autoimmun. 2015;65:1‐18.
    1. Ito M, Yamazaki S, Yamagami K, et al. A novel JAK inhibitor, peficitinib, demonstrates potent efficacy in a rat adjuvant‐induced arthritis model. J Pharmacol Sci. 2017;133(1):25‐33.
    1. O'Shea JJ, Kontzias A, Yamaoka K, Tanaka Y, Laurence A. Janus kinase inhibitors in autoimmune diseases. Ann Rheum Dis. 2013;72(Suppl 2):ii111‐ii115.
    1. Alexander SPH, et al. The Concise Guide to Pharmacology. Br J Pharmacol. 2017;174:S1‐S446.
    1. Takeuchi T, Tanaka Y, Iwasaki M, Ishikura H, Saeki S, Kaneko Y. Efficacy and safety of the oral Janus kinase inhibitor peficitinib (ASP015K) monotherapy in patients with moderate to severe rheumatoid arthritis in Japan: a 12‐week, randomised, double‐blind, placebo‐controlled phase IIb study. Ann Rheum Dis. 2016;75(6):1057‐1064.
    1. Kivitz AJ, Gutierrez‐Urena SR, Poiley J, et al. Peficitinib, a JAK inhibitor, in the treatment of moderate‐to‐severe rheumatoid arthritis in patients with an inadequate response to methotrexate. Arthritis Rheumatol. 2017;69(4):709‐719.
    1. Genovese MC, Greenwald M, Codding C, et al. Peficitinib, a JAK inhibitor, in combination with limited conventional synthetic disease‐modifying antirheumatic drugs in the treatment of moderate‐to‐severe rheumatoid arthritis. Arthritis Rheumatol. 2017;69(5):932‐942.
    1. Tanaka Y, Takeuchi T, Tanaka S, et al. Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis and an inadequate response to conventional DMARDs: a randomised, double‐blind, placebo‐controlled phase III trial (RAJ3). Ann Rheum Dis. 2019;78(10):1320‐1332.
    1. Takeuchi T, Tanaka Y, Tanaka S, et al. Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase III randomised, double‐blind, placebo‐controlled trial (RAJ4) in Japan. Ann Rheum Dis. 2019;78(10):1305‐1319.
    1. Cao YJ, Sawamoto T, Valluri U, et al. Pharmacokinetics, pharmacodynamics, and safety of ASP015K (peficitinib), a new Janus kinase inhibitor, in healthy subjects. Clin Pharmacol Drug Dev. 2016;5(6):435‐449.
    1. Shibata M, Toyoshima J, Kaneko Y, et al. The bioequivalence of two Peficitinib formulations, and the effect of food on the pharmacokinetics of peficitinib: two‐way crossover studies of a single dose of 150 mg peficitinib in healthy volunteers. Clin Pharmacol Drug Dev. 2020. 10.1002/cpdd.843
    1. Shibata M, Hatta T, Saito M, et al. Pharmacokinetics, pharmacodynamics, and safety of peficitinib (ASP015K) in healthy male Caucasian and Japanese subjects. Clin Drug Investig. 2020;40(5):469‐484.
    1. Oda K, Cao YJ, Sawamoto T, et al. Human mass balance, metabolite profile and identification of metabolic enzymes of [14C]ASP015K, a novel oral Janus kinase inhibitor. Xenobiotica. 2015;45(10):887‐902.
    1. Miyatake D, Shibata T, Toyoshima J, et al. Pharmacokinetics and safety of a single oral dose of peficitinib (ASP015K) in Japanese subjects with normal and impaired hepatic function. Clin Pharmacol Drug Dev. 2019;9(6):699‐708.
    1. Miyatake D, Shibata T, Shibata M, et al. Pharmacokinetics and safety of a single oral dose of peficitinib (ASP015K) in Japanese subjects with normal and impaired renal function. Clin Drug Investig. 2020;40(2):149‐159.
    1. Shibata M, Toyoshima J, Kaneko Y, Oda K, Nishimura T. A drug–drug interaction study to evaluate the impact of peficitinib on OCT1‐ and MATE1‐mediated transport of metformin in healthy volunteers. Eur J Clin Pharmacol. 2020;76(8):1135‐1141.
    1. Jonsson EN, Karlsson MO. Xpose–an S‐PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Meth Programs Biomed. 1999;58(1):51‐64.
    1. Gisleskog PO, Karlsson MO, Beal SL. Use of prior information to stabilize a population data analysis. J Pharmacokinet Pharmacodyn. 2002;29(5/6):473‐505.
    1. Imai E, Horio M, Nitta K, et al. Estimation of glomerular filtration rate by the MDRD study equation modified for Japanese patients with chronic kidney disease. Clin Exp Nephrol. 2007;11(1):41‐50.
    1. Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction‐corrected visual predictive checks for diagnosing nonlinear mixed‐effects models. AAPS J. 2011;13(2):143‐151.
    1. Klünder B, Mittapalli RK, Mohamed M‐EF, Friedel A, Noertersheuser P, Othman AA. Population pharmacokinetics of upadacitinib using the immediate‐release and extended‐release formulations in healthy subjects and subjects with rheumatoid arthritis: analyses of phase I–III clinical trials. Clin Pharmacokinet. 2019;58(8):1045‐1058.
    1. Admiraal R, van Kesteren C, der Zijde Jol‐van CM, et al. Population pharmacokinetic modeling of Thymoglobulin(®) in children receiving allogeneic–hematopoietic cell transplantation: towards improved survival through individualized dosing. Clin Pharmacokinet. 2015;54(4):435‐446.
    1. Sun Y‐N, Lu J‐F, Joshi A, Compton P, Kwon P, Bruno RA. Population pharmacokinetics of efalizumab (humanized monoclonal anti‐CD11a antibody) following long‐term subcutaneous weekly dosing in psoriasis subjects. J Clin Pharmacol. 2005;45(4):468‐476.
    1. McLachlan AJ, Tett SE. Pharmacokinetics of fluconazole in people with HIV infection: a population analysis. Br J Clin Pharmacol. 1996;41(4):291‐298.

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