Reduction of dietary fat absorption by the novel gastrointestinal lipase inhibitor cetilistat in healthy volunteers.
OBJECTIVE
To assess the efficacy, pharmacodynamics, safety and tolerability of a range of doses of cetilistat, a novel inhibitor of gastrointestinal lipases, in healthy volunteers.


METHODS
Three Phase I, randomized, placebo-controlled, parallel-group studies were conducted. Enrolled subjects in the three studies (n = 99) received a controlled calorie diet (total intake 2160 calories daily, 30% from fat). Twenty-four subjects were randomized to placebo and 66 were randomized to the following cetilistat doses: 50 mg three times daily [t.i.d. (n = 7)], 60 mg t.i.d. (n = 9), 100 mg t.i.d. (n = 7), 120 mg t.i.d. (n = 9), 150 mg t.i.d. (n = 16), 240 mg t.i.d. (n = 9) and 300 mg t.i.d. (n = 9). Nine subjects received the approved orlistat dose (120 mg t.i.d.). Treatment was for 5 days, with a 2-day run-in period and 1-day post-treatment follow-up. The primary outcome measure was daily faecal fat excretion. Secondary outcomes included plasma lipid levels, tolerability [gastrointestinal adverse events (AEs)] and safety.


RESULTS
Cetilistat increased faecal fat excretion relative to baseline at all doses. Cetilistat was well tolerated, with gastrointestinal AEs the most common (51%). Steatorrhoea (oily stool) was more frequent in the orlistat group (4.11 events per subject) than in any cetilistat dose group (0.14-1.81 events per subject). Most AEs (98%) were mild or moderate in intensity.


CONCLUSIONS
Cetilistat increased dietary fat excretion in healthy volunteers receiving a controlled calorie diet. Cetilistat was well tolerated at all doses examined and tolerability appeared to be improved relative to orlistat. Faecal fat excretion in the cetilistat groups was at least comparable to the orlistat 120 mg t.i.d. group.
Bryson
Andrew
A
Alizyme Therapeutics Ltd, Great Abington, Cambridge, UK. andrew.bryson@alizyme.com
de la Motte
Stephan
S
Dunk
Christopher
C
D000293:Adolescent; D000328:Adult; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D048588:Benzoxazines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004041:Dietary Fats / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D007783:Lactones / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D008049:Lipase / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000188:drug therapy; D000077403:Orlistat; D016896:Treatment Outcome; D055815:Young Adult
D019440:Anti-Obesity Agents; D048588:Benzoxazines; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D007783:Lactones; D000077403:Orlistat; D008049:Lipase; C520092:cetilistat