Impact of Food and Beverage on Enlicitide Pharmacokinetics and LDL-C Lowering.

Abstract

Enlicitide decanoate is a macrocyclic peptide first-in-class oral PCSK9 inhibitor that lowers LDL-C, with maximal efficacy achieved when administered on an empty stomach. This work characterizes the effects of food, pre-dose fasting duration (2-8 hours), water volume, common beverages (black coffee and plain tea), and other real-world scenarios on enlicitide exposure and predicts the impact on clinical efficacy. Three phase I, open-label, crossover studies in healthy participants evaluated the effects of these conditions on enlicitide exposure following a single 20 mg dose. Enlicitide steady-state exposure and corresponding LDL-C reductions under various conditions were predicted using population pharmacokinetic and exposure-response models. Administration of enlicitide 30 minutes after a high-fat meal resulted in an approximately 48% reduction in steady-state AUC and delayed absorption compared with fasted conditions (median Tmax ~8 hours vs. 0.5-1 hour). Increasing pre-dose fasting duration from 2 to 8 hours increased exposure. Water volume, black coffee or plain tea had no meaningful effect on enlicitide exposure. Model-predicted LDL-C reductions remained robust across various conditions, with LDL-C reductions of approximately 64% under fasted conditions, 62% to 63% when occasionally administered with food or if a dose is occasionally missed, 60% with black coffee or plain tea, and 59% following a 4-hour fast. These data support the recommended dosing and administration instructions for enlicitide, which are expected to provide ~60% LDL-C reduction, as seen in the enlicitide phase III clinical trials. Furthermore, these findings highlight the pharmacokinetic forgiveness potential of enlicitide, suggesting that occasional departures from the recommended dosing or sporadic lapses in compliance may be tolerated with minimal impact on efficacy.