Pharmacodynamic effects of a novel prokinetic 5‐HT₄ receptor agonist, ATI‐7505, in humans

Abstract

ATI-7505, an investigational 5-HT(4) receptor agonist, was designed to have similar activity as cisapride without the cardiac adverse effects, i.e. without QT prolongation. In addition, ATI-7505 is not metabolized by CYP450. The aim of the study was to assess the effect of ATI-7505 on gastrointestinal (GI) and colonic transit in healthy humans. A randomized, parallel-group, double-blind, placebo-controlled study evaluated effects of 9-day treatment with ATI-7505 (3, 10 or 20 mg t.i.d.) on scintigraphic GI and colonic transit in healthy volunteers (12 per group). Primary endpoints were gastric-emptying (GE) T(1/2), colonic geometric centre (GC) at 24 h and ascending colon (AC) emptying T(1/2). Daily stool diaries were kept. Analysis of covariance assessed overall treatment group differences, followed by post hoc unadjusted pairwise comparisons. There were borderline overall treatment effects (decrease) on GE T(1/2) (P = 0.154); the 20 mg t.i.d. of ATI-7505-accelerated GE vs placebo (P = 0.038). ATI-7505 increased colonic transit (GC24, P = 0.031) with fastest transit at 10 mg t.i.d. vs placebo (P = 0.065). ATI-7505 accelerated AC emptying T(1/2) (overall P = 0.075) with 10 mg dose vs placebo (P = 0.042). There was looser stool (Bristol stool form scale, overall P = 0.056) with the 10 and 20 mg t.i.d. doses. No safety issues were identified. ATI-7505 accelerates overall colonic transit and tends to accelerate GE and AC emptying and loosen stool consistency.

Novel and Validated Approaches for Gastric Emptying Scintigraphy in Patients with Suspected Gastroparesis

“…This observation highlights the unresolved question of whether the low-fat, EggBeaters meal is even the optimal solid meal substrate; indeed, significantly different emptying between the EggBeaters meal and a radiolabeled liver at 3 h was reported in the original report ''validating'' the EggBeaters meal [1]. GES also has utility in the evaluation of the motility effects of drugs, such as has been reported for studies utilizing the 2 % fat EggBeaters meal [7,8] and with the higher-calorie (296 kcal) and 32 % fat scrambled eggs meal [9,10].…”

“…Gastric emptying curves for liquid and solid meals were derived based on data from the available literature (references 1, 2, 4, 5, and 6 in the paper) healthy individuals should inform future investigations regarding whether the EggBeaters meal is optimal for the assessment of GE in patients with upper gastrointestinal symptoms. While the Ensure Plus meal may be useful in conducting GES in patients unable to tolerate a solid meal, the published validation data [4] and responsiveness to pharmacological therapy [9,10] suggest that an alternative meal of higher caloric and fat content should be used to assess GE in the majority of patients with upper gastrointestinal symptoms.…”

“…Such a test meal with two eggs, 296 kcal, and 32 % fat content has been extensively validated in the literature, including detailed performance characteristics in large healthy populations [4], responsiveness to treatment with pharmacological agents [9,10], and demonstrated utility in the clinical practice of three Mayo Clinic sites for over two decades. These studies also demonstrated that the gastrointestinal tract of healthy females empties on average 15 % slower than males [4], an observation that should be factored into the interpretation of GE data.…”

Core Aspects of Clinical Development and Trials in Chronic Idiopathic Constipation

“…These studies have utilized scintigraphic techniques in patients and healthy volunteers (Degen et al, 2001(Degen et al, , 2005Camilleri et al, 2007;Manini et al, 2010;Talley et al, 2006). Endpoints have included colonic transit time (GC24), ascending colon emptying (ACE) T 1/2 , gastric emptying (GE) time and colonic filling at 6 hours (CF6).…”

“…Naronapride (ATI-7505) is a 5-HT 4 receptor agonist belonging to the benzamide series of similar compounds (Camilleri et al, 2007). The design of naronapride was based on the prototypical benzamide agent, cisapride.…”