Development of a Prototype, Once-Daily, Modified-Release Formulation for the Short Half-Life RIPK1 Inhibitor GSK2982772

Debra J Tompson, Mark Whitaker, Rennan Pan, Geoffrey Johnson, Teresa Fuller, Litza McKenzie, Vanessa Zann, Marcy Powell, Kathy Abbott-Banner, Simon Hawkins, Debra J Tompson, Mark Whitaker, Rennan Pan, Geoffrey Johnson, Teresa Fuller, Litza McKenzie, Vanessa Zann, Marcy Powell, Kathy Abbott-Banner, Simon Hawkins

Abstract

Purpose: GSK2982772 is a selective inhibitor of receptor-interacting protein kinase-1, with a 2-3 h half-life. This study evaluated if a once-daily modified-release formulation of GSK2982772 could be developed with no significant food effect.

Methods: Part A evaluated the pharmacokinetics of GSK2982772 following fasted single-dose (120 mg) administration of two matrix minitab formulations (MT-8 h and MT-12 h) vs 120 mg immediate release (IR) and MT-12 h with a high-fat meal. Part B evaluated once-daily MT-12 h for 3 days at three dose levels. Part C evaluated a matrix monolithic (MM-12 h) formulation at two dose levels in different prandial states.

Results: All modified-release formulations dosed in the fasted state reduced maximum plasma concentration (Cmax), delayed time to Cmax, and decreased area under the curve (AUC) vs IR. When MT-12 h or MM-12 h were co-administered with a meal (standard or high-fat) Cmax and AUC increased. Dosing MM-12 h 1 h before a standard or high-fat meal had minimal impact on exposure vs fasted.

Conclusions: MT-12 h and MM-12 h provided a QD pharmacokinetic profile in the fasted state, however when MT-12 h was dosed with a high-fat meal a QD profile was not maintained. ( ClinicalTrials.gov Identifier: NCT03266172).

Keywords: GSK2982772; modified release; once-daily; pharmacokinetics; short half-life.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Simulations of steady-state concentration-time profiles of GSK2982772 for MR QD dosing, which provide similar trough concentrations as IR 60 mg BID, Solid line represents median predicted concentration-time profile and lighter shaded area represents the 95% prediction interval. BID, twice daily; IR, immediate release; MR, modified release; MR-6 h, modified release with 80% release at 6 h; MR-12 h, modified release with 80% release at 12 h; MR-15 h, modified release with 80% release at 15 h; MR-18 h, modified release with 80% release at 18 h; QD, once daily.
Fig. 2
Fig. 2
Design space for study Parts A and B.
Fig. 3
Fig. 3
Study design. (a) Part A: formulation optimization and food effect. (b) Part B: dose ranging. (c) Part C: modified-release matrix monolithic tablet formulation and food effect, IR, immediate release; Min, minimum; MM-12 h, matrix monolithic with 80% release at 12 h; MT-8 h, matrix minitablet with 80% release at 8 h; MT-12 h, matrix minitablet with 80% release at 12 h; PK, pharmacokinetic.
Fig. 4
Fig. 4
Mean (± SE) plasma GSK2982772 concentration-time profile following a single dose, by formulation and prandial state (Part A), IR, immediate release; MT-8 h, matrix minitablet with 80% release at 8 h; MT-12 h, matrix minitablet with 80% release at 12 h; SE, standard error.
Fig. 5
Fig. 5
Individual subject (geometric mean [± 95% CI]) plasma GSK2982772 AUC(0-inf), Cmax, and C24h, by formulation and prandial state (Part A). AUC(0-inf), area under the plasma concentration vs time curve zero to infinity; C24h, concentration at 24 h post-dose; CI, confidence interval; Cmax, maximum plasma concentration; IR, immediate release; MT-8 h, matrix minitablet with 80% release at 8 h; MT-12 h, matrix minitablet with 80% release at 12 h.
Fig. 6
Fig. 6
Mean (± SE) plasma GSK2982772 concentration-time profile following repeated dosing of MR MT-12 h for 3 days (Part B). MR, modified release; MT-8 h, matrix minitablet with 80% release at 8 h; MT-12 h, matrix minitablet with 80% release at 12 h; SE, standard error.
Fig. 7
Fig. 7
Geometric mean (± 95% CI) and individual observed dose-normalized exposure to GSK2982772 on day 1 and after repeated dosing on day 3 (Part B). AUC(0–24), area under the plasma concentration vs time curve from zero to 24 h; CI, confidence interval; Cmax, maximum plasma concentration; IR, immediate release; MT-12 h, matrix minitablet with 80% release at 12 h.
Fig. 8
Fig. 8
Mean (± SE) plasma GSK2982772 concentration-time profile following a single dose of MR MM-12 h (Part C), by formulation and prandial state. IR, immediate release; MM-12 h, matrix monolithic with 80% release at 12 h; MR, modified release; SE, standard error.

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