Interaction of subcutaneous lixisenatide 20 μg QD on pharmacokinetic and pharmacodynamic properties of oral ramipril 5 mg QD in steady state in young healthy males and females

摘要

Introduction: Lixisenatide is a GLP-1 agonist in development for once-daily SC administration in patients with T2DM. T2DM patients frequently receive a concomitant ACE inhibitor. We assessed the effect of multiple doses of lixisenatide on steady-state PK and PD properties of ramipril and its active metabolite ramiprilat in an open, randomized, 2X2 cross-over study.Methods: Healthy young males and females (n = 30) were randomized to one of two treatment sequences to receive 5 mg ramipril alone in one period and 5 mg ramipril plus 20 μg lixisenatide for 6 days in the other. 20 μg lixisenatide treatment was preceded by a 7-day run-in with 10 μg lixisenatide. Ramipril treatments were separated by 23-day washout periods. 24-h PK profiles of ramipril and ramiprilat were taken on Day 6 of ramipril dosing in both periods. PD response to ramipril was evaluated on the change from period baseline in AUC0-24 in each period for the tetrapeptide N-Acetyl-Ser-Asp-Lys-Pro (AcSDKP) after 6 daily doses of 5 mg ramipril alone and under co-administration with lixisenatide.