Purpose

GSK2982772 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.

Methods

Part 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.

Results

All modified-release formulations dosed in the fasted state reduced maximum plasma concentration (Cmax), delayed time to C_max, 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) C_max and AUC increased. Dosing MM-12 h 1 h before a standard or high-fat meal had minimal impact on exposure vs fasted.

Conclusions

MT-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).

中文翻译：

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开发用于短半衰期 RIPK1 抑制剂 GSK2982772 的原型、每日一次、改良释放配方

目的

GSK2982772 是受体相互作用蛋白激酶-1 的选择性抑制剂，半衰期为 2-3 小时。该研究评估了 GSK2982772 的每日一次缓释制剂是否可以开发而没有显着的食物影响。

方法

A 部分评估了 GSK2982772 在禁食单剂量（120 毫克）两种基质 minitab 制剂（MT-8 小时和 MT-12 小时）与 120 毫克立即释放 (IR) 和 MT-12 小时后的药代动力学，具有高脂肪餐。B 部分在三个剂量水平下每天评估一次 MT-12 小时，持续 3 天。C 部分在不同的膳食状态下评估了两种剂量水平的基质整体 (MM-12 h) 制剂。

结果

在禁食状态下给药的所有修饰释放制剂减小的最大血浆浓度（Cmax），延迟时间至C_最大值，和曲线（AUC）对IR下面积减小。当 MT-12 h 或 MM-12 h 与膳食（标准或高脂肪）共同给药时，C _max和 AUC 增加。与禁食相比，在标准或高脂肪餐前 1 小时服用 MM-12 小时对暴露的影响最小。

结论

MT-12 h 和 MM-12 h 在禁食状态下提供 QD 药代动力学特征，但是当 MT-12 h 与高脂肪膳食一起给药时，QD 特征并未保持。（ClinicalTrials.gov 标识符：NCT03266172）。