Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Selective 5-HT1 receptor agonists, ATC code: N02CC01.
Sumatriptan is a selective vascular 5-hydroxytryptamine-1-(5-HT1d) receptor agonist with no effect on other 5-HT receptor (5-HT2–5-HT7) subtypes. The vascular 5-HT1d receptor is found predominantly in cranial blood vessels and mediates vasoconstriction. In animals, sumatriptan selectively constricts the carotid arterial circulation, but does not alter cerebral blood flow. The carotid arterial circulation supplies blood to the extracranial and intracranial tissues such as the meninges and dilatation and/or oedema formation in these vessels is thought to be the underlying mechanism of migraine in man. In addition, evidence from animal studies suggests that sumatriptan inhibits trigeminal nerve activity. Both cranial vasoconstriction and inhibition of trigeminal nerve activity may contribute to the anti-migraine action of sumatriptan in humans.
Clinical response begins 15 minutes following a 20 mg dose given by intranasal administration.
Because of its route of administration, Imitrex Nasal Spray may be particularly suitable for patients who suffer nausea and vomiting during a migraine attack.
The magnitude of treatment effect is smaller in adolescents compared with adults.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
After intranasal administration, sumatriptan is rapidly absorbed, median times to maximum plasma concentrations being 1.5 (range: 0.25-3) hours in adults and 2 (range: 0.5-3) hours in adolescents. After a 20 mg dose, the mean maximum concentration is 13ng/mL. Mean intranasal bioavailability, relative to subcutaneous administration is about 16%, partly due to pre-systemic metabolism.
Plasma protein binding is low (14–21%) and the mean volume of distribution is 170L. The elimination half-life is approximately 2 hours. The mean total plasma clearance is approximately 1160mL/min and the mean renal plasma clearance is approximately 260mL/min.
A pharmacokinetic study in adolescent subjects (12–17 years) indicated that the mean maximum plasma concentration was 13.9ng/mL and mean elimination half-life was approximately 2 hours following a 20 mg intranasal dose. Population pharmacokinetic modelling indicated that clearance and volume of distribution both increase with body size in the adolescent population resulting in higher exposure in lower bodyweight adolescents.
Non-renal clearance accounts for about 80% of the total clearance. Sumatriptan is eliminated primarily by oxidative metabolism mediated by monoamine oxidase A. The major metabolite, the indole acetic acid analogue of sumatriptan, is mainly excreted in urine, where it is present as a free acid and the glucuronide conjugate. It has no known 5-HT1 or 5-HT2 activity. Minor metabolites have not been identified. The pharmacokinetic profile of intranasal sumatriptan does not appear to be significantly affected by migraine attacks.

Special Patient Populations

Elderly (over 65)
The kinetics in the elderly have been insufficiently studied to justify a statement on possible differences in kinetics between elderly and young volunteers.
Hepatic impairment


Sumatriptan pharmacokinetics after an oral dose (50 mg) and a subcutaneous dose (6 mg) were studied in 8 patients with mild to moderate hepatic impairment matched for sex, age, and weight with 8 healthy subjects. Following an oral dose, sumatriptan plasma exposure (AUC and Cmax) almost doubled (increased approximately 80%) in patients with mild to moderate hepatic impairment compared to the control subjects with normal hepatic function. There was no difference between the patients with hepatic impairment and control subjects after the s.c. dose.
This indicates that mild to moderate hepatic impairment reduces presystemic clearance and increases the bioavailability and exposure to sumatriptan compared to healthy subjects.
Following oral administration, pre-systemic clearance is reduced in patients with mild to moderate hepatic impairment and plasma exposure, measured by Cmax and AUC, almost doubled. Since a portion of the nasal spray dose is swallowed, patients with mild to moderate hepatic impairment could also have higher exposures, but to a lesser extent than observed after oral dosing. (see Section 4.4, Warnings and Precautions).
The pharmacokinetics of sumatriptan in patients with severe hepatic impairment have not been studied (see Section 4.3 Contraindications and Section 4.4 Warnings and Precautions).