SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF SUMATRIPTAN IN HEALTHY-SUBJECTS FOLLOWING ASCENDING SINGLE INTRANASAL DOSES AND MULTIPLE INTRANASAL DOSES

The delivery of sumatriptan doses intranasally could add greater flexi bility in the treatment of migraine than is possible with the currentl y available subcutaneous and oral sumatriptan preparations. Two indepe ndent double-blind, randomized, placebo-controlled clinical studies we re conducted to evaluate the safety, tolerability and pharmacokinetics of intranasally administered sumatriptan following ascending single d oses (three different dose levels) and multiple doses. In the four-way , crossover, ascending-dose study, 20 healthy female subjects were ran domized to receive on separate occasions single intranasal spray doses of 5, 10, or 20 mg sumatriptan (as the hemisulphate salt) or placebo into one nostril. Adverse events were mild and consisted mainly of bit ter taste at the back of the throat and events typical of sumatriptan administered by other routes (headache, lightheadedness and tingling). Area under the plasma sumatriptan concentration versus time curve (AU C(infinity)) and peak plasma concentration (C-max) increased with the dose. Dose proportionality was demonstrated between 5 and 10 mg but no t across the dose range 5-20 mg. Time to maximum plasma concentration (t(max)) was variable due to multiple peaking. The elimination half-li fe (t(1/2)), approximately 2 h, was unaffected by the magnitude of dos e. In the two-period, multiple-dose, crossover study, 12 healthy adult male and female subjects were randomized to receive either sumatripta n hemisulphate 20 mg or placebo, administered intranasally as a spray three times a day for 4 days. The two dosing periods were separated by 3 to 14 days. Multiple doses of sumatriptan were well tolerated, with no serious adverse events occurring or withdrawals due to adverse eve nts. All patients reported a mild to moderate drug-related disturbance of taste. Nasal examinations remained normal, and olfactory function was unaffected. The AUC over the first 8 h following dosing (AUC(8)) a nd fraction of the dose excreted in the urine (f(e); 6.2% vs 3.6%) wer e similar on Days 1 and 4. Day 4 values were significantly higher (p l ess than or equal to 0.05) for C-max (16.9 ng/ml vs 13.1 ng/ml), renal clearance (Cl-I; 19.01/h vs 14.21/h). and t(1/2) (2.18 h vs 1.93 h), and shorter for t(max) (0.88 h vs 1.75 h). Some accumulation (22%) occ urred over the 4 days of dosing. Serum concentrations of the pharmacol ogically inactive indole acetic acid metabolite of sumatriptan were fo urfold to fivefold higher than corresponding sumatriptan concentration s. Overall, these studies show that the sumatriptan intranasal spray f ormulation is well tolerated, allows rapid absorption of sumatriptan, and results in only a clinically insignificant degree of sumatriptan a ccumulation upon repeated dosing.