Development of a Once-Daily Modified-Release Formulation for the Short Half-Life RIPK1 Inhibitor GSK2982772 using DiffCORE Technology

by Selleckchem | Dec 05 2023

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).

Comments:

Based on the provided information, it appears that the study aimed to evaluate the safety and pharmacokinetics (PK) of different modified-release (MR) formulations of GSK2982772, a selective inhibitor of receptor-interacting protein kinase-1 (RIPK1). The previous matrix monolithic formulation provided a once-daily (QD) PK profile over 12 hours but was affected by food. The current study used GSK proprietary DiffCORE™ technology to create MR formulations with varying release profiles (ranging from 12 to 18 hours) and assessed their PK and safety in both fasted and fed states.

**Methods:**
- **Part A:** Investigated PK after single-dose administration (240 mg) of three DiffCORE MR formulations (ranging from 80% GSK2982772 released over 12 hours to 80% GSK2982772 released over 18 hours) in both fasted and fed (high-fat meal) states. A comparison with an immediate-release formulation was made.

- **Part B:** Evaluated the MR-16 h formulation at different doses (ranging from 120 to 960 mg) in various prandial states.

**Results:**
- **PK Profiles:** The PK profiles for all MR formulations and doses in both fasted and fed states were consistent with once-daily dosing.

**Conclusions:**
- **DiffCORE Technology:** The DiffCORE technology successfully addressed the vulnerability to food effects observed with the previous matrix monolithic formulation.

- **Formulation Selection:** The MR-16 h formulation (doses ranging from 120 to 960 mg) was chosen for further clinical development as a once-daily dosing regimen. The study's clinical trial identifier is NCT03649412 (registered on September 26, 2018).

In summary, the study demonstrated that the DiffCORE technology provided a stable once-daily PK profile for GSK2982772, overcoming the challenges related to food effects. This finding was pivotal in selecting the MR-16 h formulation for continued clinical development, signifying its potential as a once-daily treatment option.