Randomized controlled phase Ib study of ghrelin agonist, RM-131, in type 2 diabetic women with delayed gastric emptying: Pharmacokinetics and pharmacodynamics

摘要

OBJECTIVE - To investigate the pharmacokinetics (PK), pharmacodynamics, and safety of single-dose RM-131 in type 2 diabetic patients with gastrointestinal cardinal symptoms (GCSI) and previously documented delayed gastric emptying (DGE). RESEARCH DESIGN AND METHODS - In a randomized crossover study, 10 female patients received RM-131 (100 μg s.c.) or placebo and underwent scintigraphic gastric emptying (GE) and colonic filling at 6 h (CF6) of a solid-liquid meal administered 30 min postdosing. Adverse events, plasma glucose, and hormonal levels were assessed. GCSI daily diary (GCSI-DD) was completed during treatments. PK was assessed in this cohort and healthy volunteers (HVs). RESULTS - At screening, HbA1c was 7.2 ± 0.4% (SEM) and total GCSI-DD score was 1.32 ± 0.21. RM-131 accelerated GE t1/2 of solids (P = 0.011); mean difference (Δ) in solid GE t1/2 was 68.3 min (95% CI 20-117) or 66.1%. There were numerical differences in GE lag time, CF6 solids, and GE t1/2 liquids (all P < 0.14). With a signifi cant (P < 0.014) order effect, further analysis of the first treatment period (n = 5 per group) con fi rmed significant RM-131 effects on GE t1/2 (solids, P = 0.016; liquids, P = 0.024;CF6, P = 0.013). PK was similar in DGE patients and HVs. There were increases in 120-min blood glucose (P = 0.07) as well as 30-90-min area under the curve (AUC) levels of growth hormone, cortisol, and prolactin (all P < 0.02) with single-dose RM-131. Only light-headedness was reported more on RM-131. CONCLUSIONS - RM-131 greatly accelerates the GE of solids in patients with type 2 diabetes and documented DGE. PK is similar in diabetic patients and HVs.