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

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

doi:10.1007/s11095-021-03059-z

Abstract

PurposeGSK2982772 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.MethodsPart 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.ResultsAll 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.ConclusionsMT-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).

Highlights

mg 80% release at 12 h (MT-12 h) and matrix monolithic (MM)-12 h provided a QD pharmacokinetic profile in the fasted state, when MT12 h was dosed with a high-fat meal a QD profile was not maintained. (ClinicalTrials.gov Identifier: NCT03266172)
GSK2982772 is a highly selective receptor-interacting protein kinase-1 (RIPK1) inhibitor being developed for the treatment of plaque psoriasis and other inflammatory diseases
The pharmacokinetic (PK) profile of GSK2982772 when administered as standard tablet or powder-in-capsule is characterized by rapid absorption, with a median time to maximum concentration (Tmax) of approximately 2 h post-dose

Summary

Introduction

GSK2982772 is a highly selective receptor-interacting protein kinase-1 (RIPK1) inhibitor being developed for the treatment of plaque psoriasis and other inflammatory diseases. RIPK1 exerts its signalling functions through its kinase activity as well as through its scaffolding function, which facilitates other immune processes including tumor necrosis factormediated classical apoptosis and nuclear factor kappa-lightchain-enhancer of activated B cell signalling [1,2,3]. Inhibitors of RIPK1 activity such as GSK2982772 are being investigated in diseases linked to tumor necrosis factor activation [4]. Biopharmaceutics Classification System class 2 drugs are generally well absorbed, but may be subject to solubility rate-limiting absorption. For GSK2982772, there is no evidence of dissolution rate-limiting absorption up to a dose of 240 mg administered either as standard immediaterelease (IR) tablets or powder-in-capsule [6,7]. The pharmacokinetic (PK) profile of GSK2982772 when administered as standard tablet or powder-in-capsule is characterized by rapid absorption, with a median time to maximum concentration (Tmax) of approximately 2 h post-dose. Because most of the systemic exposure is associated with the 2–3 h t1⁄2, initial clinical trials conducted with GSK2982772 have used twice-daily (BID) and thricedaily (TID) regimens with IR 60-mg tablets [8]

Methods

Results

Discussion

Conclusion