Safety, Tolerability and Pharmacokinetics of Single Rising Doses of YF476, a Gastrin Antagonist, in Healthy Men
The objectives of the study were:
- To assess the safety, tolerability and pharmacokinetics of YF476 in healthy volunteers.
- To select a dose or doses of YF476 for detailed pharmacodynamic studies in healthy volunteers.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Basic Science
|Official Title:||A Double-blind, Placebo-controlled Study to Assess the Safety, Tolerability and Pharmacokinetics of Single Rising Oral Doses of YF476, a Novel, Potent and Selective Gastrin/Cholecystokinin-B Antagonist, in Healthy Male Volunteers|
- Clinically relevant changes from baseline in safety assessments [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]Physical examination, ECG and safety tests of blood and urine at screening and at 24 hours and 7 days after dosing. ECG, blood pressure and heart rate during study period.
- Numbers of adverse events [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]Adverse events during study period and at follow-up.
- Pharmacokinetic parameters: Cmax, Tmax, AUC 0-24 h, T1/2 [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
Blood samples (10 mL) for assay of YF476 at 0, 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours after dosing.
Urine collection: 0-6, 6-12 and 12-24 hours after dosing.
|Study Start Date:||May 1996|
|Study Completion Date:||June 1996|
|Primary Completion Date:||June 1996 (Final data collection date for primary outcome measure)|
Two groups of six subjects received single rising oral doses of YF476 capsules or matching placebo. Each subject received 2 doses of YF476 and 1 dose of placebo. 4 subjects received active and 2 placebo at each dose level, as follows:
Group A YF476 0.5, 25 and 100mg by mouth Group B YF476 5.0, 50 and 100mg by mouth
Groups A & B were dosed alternately, at weekly intervals
YF476 is clearly a potent and selective gastrin/CCK-B antagonist and should inhibit basal and meal-stimulated gastric acid secretion and enhance gastric emptying of a liquid meal in man. Therefore YF476 might benefit patients with reflux oesophagitis. The compound has been remarkably well tolerated in animal toxicity studies at doses well in excess of the projected therapeutic dose in patients, and merits first administration to healthy volunteers. That study using the oral route of administration is described here. Extrapolation from data obtained with pentagastrin in animals suggest that single doses of less than 1mg of YF476 should be active in man. However, extrapolation from data obtained in comparative studies with the H2-antagonists and with omeprazole in animals suggest that the therapeutic dose in patients with reflux oesophagitis will be larger, in the region of 10mg. A range of single doses will be used in this study. The maximum dose will be 10 times more than the expected therapeutic dose.
|Hammersmith Medicines Research|
|London, United Kingdom, NW10 7EW|
|Study Director:||Malcolm J Boyce, FRCP FFPM||Trio Medicines Limited|