Development of a Once-Daily Modified-Release Formulation for the Short Half-Life RIPK1 Inhibitor GSK2982772 using
Debra Tompson1, Mark Whitaker2, Rennan Pan3
1Clinical Pharmacology Modelling and Simulation, Medicines Research Centre, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, Hertfordshire, UK. debra.j.tompson@gsk.com.
Purpose:
GSK2982772 is a selective inhibitor of receptor-interacting protein kinase-1 (RIPK1) with a short 2- to 3-h half-life. In a previous modified-release (MR) study, a matrix monolithic formulation (80% GSK2982772 released over 12 h) provided a once-daily (QD) pharmacokinetic (PK) profile in the fasted state; however, it was susceptible to food effects. The current study evaluated the safety and PK of MR formulations using GSK proprietary DiffCORE™ technology.
Methods:
Part A evaluated PK following single-dose (240 mg) fasted and fed (high-fat meal) administration of three DiffCORE MR formulations within pre-defined in vitro extremes of 80% GSK2982772 released over 12 h (MR-12 h) to 80% GSK2982772 released over 18 h (MR-18 h) versus an immediate-release formulation. Part B evaluated MR-16 h (120-960 mg) in different prandial states.
Results:
Pharmacokinetic profiles for all MR formulations and doses tested in the fasted and fed states were consistent with QD dosing.
Conclusions:
The DiffCORE technology overcame the food effect vulnerability observed with the matrix monolithic formulation. The MR-16 h formulation was selected for further clinical development as a QD dosing regimen (NCT03649412 September 26, 2018).
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