SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF SUMATRIPTAN SUPPOSITORIES FOLLOWING SINGLE AND MULTIPLE DOSES IN HEALTHY-VOLUNTEERS

A suppository formulation of the 5HT(1) agonist sumatriptan could prov e an important therapeutic option in migraine patients who dislike or poorly tolerate injectable therapy and where oral tablet administratio n is unsuitable because of severe migraine-related vomiting. Two indep endent double-blind, randomized clinical studies were conducted to eva luate the safety, tolerability and pharmacokinetics of sumatriptan sup positories following ascending single doses (four different dose level s) and multiple doses. In the four-period, crossover, single-dose stud y, 24 healthy male subjects were randomized to receive a suppository c ontaining 12.5, 25, 50, or 100 mg on separate occasions 3-14 days apar t. The suppositories were generally well tolerated; transient asthenia , drowsiness, and headache were the most frequently reported adverse e vents, and these were not dose-related. Peak plasma concentrations (C- max) of sumatriptan were proportional to dose from 25 to 100 mg; area under the plasma concentration-time curve (AUC(infinity)) values were proportional to dose except at the highest doses, when they were great er than those predicted from lower doses. For all doses, the t(max) of sumatriptan occurred within 2.5 h, and the t(1/2) was approximately 2 h. In the two-period, placebo-controlled. crossover, repeat-dose stud y, 12 healthy adult male subjects were randomized to receive either a 50-mg sumatriptan suppository or placebo suppository, administered rec tally twice a day for 11 doses (51/2 days). Adverse events were no mor e frequent with sumatriptan than with placebo, and stool guaiac, recta l examinations, and physical examinations remained normal. No signific ant differences were noted between Day 1 and Day 6 values in the AUG, C-max, time of peak serum concentration (t(max)), elimination half-lif e (t(1/2)), fraction of the dose excreted in the urine (f(e)), or rena l clearance (Cl-r) of sumatriptan or its pharmacologically inactive in dole acetic acid metabolite. Serum metabolite concentrations were two to threefold higher than corresponding sumatriptan concentrations. No clinically significant accumulation of sumatriptan or its metabolite o ccurred. Overall, these studies show that sumatriptan administration v ia a suppository formulation is well tolerated, allows rapid absorptio n of sumatriptan, results in sumatriptan C-max values that are proport ional to dose from 25 to 100 mg, and is not associated with accumulati on of sumatriptan or its metabolite.