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

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

Abstract

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).

Keywords: DiffCORE; GSK2982772; RIPK1; modified release; translational pharmaceutics.

Conflict of interest statement

DT, MW, RP, GJ, TF, KA-B, and MP are employees of and hold equity stock in GlaxoSmithKline (GSK). SH is a former employee of and stockholder in GSK. VZ and LM are employees of Quotient Sciences Limited, where the study was conducted.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Study design. (a) Part A Formulation Optimization and Food Effect (b) Part B Tablet Strength and Food Effect. h, hours; IR, intermediate release; MR-12 h, modified release with 80% release at 12 h; MR-16 h, modified release with 80% release at 16 h; MR-18 h, modified release with 80% release at 18 h. aTablet manufactured without apertures (non-drilled).
Fig. 2
Fig. 2
Mean plasma GSK2982772 concentration–time plots by formulation (fasted) and prandial state (Part A) for 240-mg dose. h, hours; IR, intermediate release; MR-12 h, modified release with 80% release at 12 h; MR-16 h, modified release with 80% release at 16 h; MR-18 h, modified release with 80% release at 18 h. Error bars represent ± 1 standard error.
Fig. 3
Fig. 3
Individual subject (geometric mean and 95% CI) plasma PK parameters by formulation and prandial state (Part A). (a) Plasma AUC(0-inf) (h*µg/mL). (b) Plasma Cmax (µg/mL). (c) Plasma C24h (µg/mL) CI, confidence interval; h, hours; IR, intermediate release; MR-12 h, modified release with 80% release at 12 h; MR-16 h, modified release with 80% release at 16 h; MR-18 h, modified release with 80% release at 18 h.
Fig. 4
Fig. 4
Mean plasma GSK2982772 concentration–time plots (Part B). (a) Concentration–Time by Dose and Prandial State. (b) DiffCORE MR-16 h 480 mg Fed (high-fat) and Enteric-Coated MR-16 h 480 mg Fed (high-fat) h, hours; MR-16 h, modified release with 80% release at 16 h. Error bars represent ± 1 standard error.
Fig. 5
Fig. 5
Individual subject GSK2982772 plasma concentration–time profiles for 480-mg MR-16 h dose. h, hours; MR-16 h, modified release with 80% release at 16 h.

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Source: PubMed

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