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

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 C-max, 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) C-max 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.