Comparison of the Pharmacokinetics of RIPK1 Inhibitor GSK2982772 in Healthy Western and Japanese Subjects

Abstract

Background and objectives: GSK2982772 is an oral small-molecule RIPK1 inhibitor with potential therapeutic efficacy in immune-mediated inflammatory diseases (IMIDs). An inter-ethnic comparison of GSK2982772 pharmacokinetics was conducted based on data from Western (Study 1) and Japanese subjects (Study 2).

Methods: Both studies were single-centre, randomised, double-blind, placebo-controlled studies with objectives to assess the safety and characterise the pharmacokinetics of GSK2982772. Western subjects in Study 1 (NCT03305419), Part A (N = 15), were randomly assigned to receive 120 mg three times daily (TID), 240 mg TID, or 360 mg twice daily (BID) doses of GSK2982772, or placebo (TID or BID) for 1 day. Part B subjects (N = 47) received GSK2982772 120 mg TID, 240 mg TID, or placebo TID for 14 days. Japanese subjects in Study 2 (N = 13) (NCT03590613) were randomly assigned to receive TID doses of GSK2982772 60, 120, 240 mg TID or placebo TID for 1 day.

Results: GSK2982772 was well tolerated and adverse events were generally mild. Maximum observed plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma drug concentration versus time curve after the first GSK2982772 dose (AUC(0-7)) of 120 and 240 mg, and (AUC(0-24)) values for the 120 and 240 mg TID doses over a single day were similar in Japanese and Western subjects.

Conclusions: The pharmacokinetics and tolerability of GSK2982772 were similar between Western and Japanese subjects, justifying inclusion of Japanese subjects in future global clinical studies to assess the therapeutic potential of RIPK1 inhibition for the treatment of IMIDs. Clinical Trials: NCT03305419 and NCT03590613 available from http://www.clinicaltrials.gov .

Conflict of interest statement

Debra J. Tompson, Carwyn Davies, Nicola E. Scott, Edward P. Cannons, Annette S. Gross, Marcy Powell, Ryutaro Shimamura, Takashi Nagakubo, Atsushi Nakano are employees of and hold equity stock in GlaxoSmithKline. Hirofumi Ogura and Harue Igarashi are employees of GSK. Michalis Kostapanos is an NHS consultant working with a 50% secondment in GSK’s Clinical Unit Cambridge and has no other relevant conflicts of interests for this study. Hiroko Ino is a former employee of GSK.

Figures

Fig. 1

Design of the Western (Study 1) and Japanese (Study 2) studies. A fifth cohort (360 mg BID) was planned in Study 1 but was not conducted because one subject in cohort 1 exceeded the Cmax stopping criteria at the 360 mg BID dose level. aA 7-day washout period was required between each single-day dosing period in Study 1, Part A, and Study 2. bEach cohort in Part B included different subjects. BID twice daily, Cmax maximum blood/plasma concentration, TID three times daily

Fig. 2

Number of subjects. a Western subjects, b Japanese subjects. Once an allocation number was assigned to a subject, it was not reassigned to any other subject. When a subject prematurely discontinued the study, replacement subjects were recruited and assigned to the same sequence as the replaced subject

Fig. 3

Plasma GSK2982772 concentration-time profiles (arithmetic mean ± SD) for 120 mg TID and 240 mg TID in Western subjects. SD standard deviation, TID three times daily

Fig. 4

Plasma GSK2982772 concentration-time profiles (arithmetic mean ± SD) in healthy Western and Japanese subjects. a 120 mg TID. b 240 mg TID. SD standard deviation, TID three times daily

Fig. 5

Comparison of GSK2982772 Cmax, AUC(0–7), and AUC(0–24) in healthy Western and Japanese subjects. aCmax after first dose of GSK2982772. b AUC(0–7) after first dose of GSK2982772. c AUC(0–24). Boxes represent the 25th–75th percentiles with median shown and whiskers represent the 10th–90th percentiles with individual data points superimposed. AUC(0–7) area under the plasma concentration-time curve from time 0 to 7 h, AUC(0–24) area under the plasma concentration-time curve from time zero to 24 h, BID twice daily, Cmax maximum plasma concentration, TID three times daily