SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF SUMATRIPTAN IN HEALTHY-SUBJECTS FOLLOWING ASCENDING SINGLE INTRANASAL DOSES AND MULTIPLE INTRANASAL DOSES
Khp. Moore et al., SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF SUMATRIPTAN IN HEALTHY-SUBJECTS FOLLOWING ASCENDING SINGLE INTRANASAL DOSES AND MULTIPLE INTRANASAL DOSES, Cephalalgia, 17(4), 1997, pp. 541-550
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.