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

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).

Monolithic stabilized finite element method for rigid body motions in the incompressible Navier-Stokes flow

We propose a new immersed volume method for solving rigid body motions in the incompressible Navier-Stokes flow. The used monolithic formulation gives rise to an extra stress tensor in the Navier-Stokes equations coming from the presence of the structure in the fluid. The system is solved using a finite element variational multiscale (VMS) method, which consists in here of a decomposition for both the velocity and the pressure fields into coarse/resolved scales and fine/unresolved scales. The distinctive feature of the proposed approach resides in the efficient enrichment of the extra constraint. We assess the behaviour and accuracy of the proposed formulation in the simulation of 2D and 3D examples.