Clinical pharmacodynamics of SDZ HTF 919, a new 5-HT4 receptor agonist, in a model of slow colonic transit

Objectives: To explore the pharmacodynamic effects of the new promotile agent SDZ HTF 919, a selective partial 5-HT4, receptor agonist, in healthy subjects. Methods: A pharmacodynamic model was applied to prolong colonic transit by dietary means. Subsequently, the effects of twice-daily multiple doses of SDZ HTF 919 (1, 5, 25, and 100 mg) were investigated in a randomized, double-blind, placebo-controlled parallel-group study with 12 subjects per dose level. The sequential design with three study periods of 7 days each included intake of a self-selected diet, a Liquid formula diet with soluble fiber supplementation, and a fiber-supplemented diet together with either SDZ HTP 919 or placebo administration. Stool characteristics (frequency and consistency) and total colonic transit times (with use of radiopaque markers) were recorded in each study period. Results: SDZ HTP 919 was well tolerated at all dose levels. The frequency of loose stool and headache increased with higher doses. After a fiber-supplemented diet intake, the median stool frequency decreased from 81/2-9 to 5-7 defecations per study period. SDZ HTP 919 in doses of 25 and 100 mg twice a day increased the stool frequency (p < 0.05). Stool consistency was softened by all but the lowest SDZ HTP 919 dose. A fiber-supplemented diet prolonged total colonic transit time in all groups by 45 hours on average. Twice-a-day administration of SDZ HTP 919 for 6 days in addition to a fiber-supplemented diet significantly shortened the total colonic transit time only at the 5 mg dose. The lack of effect at lower and higher SDZ HTP 919 doses suggests a biphasic dose-response relationship for total colonic transit time. Conclusions: The suitability of total colonic transit time measurements in healthy subjects as a surrogate marker should be confirmed by patient studies.