Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1       Pharmacodynamic properties
Pharmacotherapeutic group: Analgesics: Selective 5-HT1 receptor agonists.

ATC code: N02CC01

Sumatriptan has been demonstrated to be a specific and selective 5- Hydroxytryptamine1 (5HT1D) receptor agonist with no effect on other 5HT 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 of 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 these actions (cranial vasoconstriction and inhibition of trigeminal nerve activity) may contribute to the anti-migraine action of sumatriptan in humans.

Sumatriptan remains effective in treating menstrual migraine i.e. migraine without aura that occurs between 3 days prior and up to 5 days post onset of menstruation. Sumatriptan should be taken as soon as possible in an attack.

Clinical response begins around 30 minutes following a 100mg oral dose.

Although the recommended dose of oral sumatriptan is 50mg, migraine attacks vary in severity both within and between patients. Doses of 25-100mg have shown greater efficacy than placebo in clinical trials, but 25mg is statistically significantly less effective than 50 and 100mg.

A number of placebo-controlled clinical studies assessed the safety and efficacy of oral sumatriptan standard tablets in over 650 child and adolescent migraineurs aged 10 - 17 years. These studies failed to demonstrate a statistically significant difference in headache relief at 2 hours between placebo and any sumatriptan dose. The undesirable effects profile of oral sumatriptan in children and adolescents aged 10 - 17 years was similar to that reported from studies in the adult population.

Pharmacokinetic Properties

5.2       Pharmacokinetic properties
Following oral administration, sumatriptan is rapidly absorbed, 70% of maximum concentration occurring at 45 minutes. After 100mg dose, the maximum plasma concentration is 54ng/ml.               Mean absolute oral bioavailability is 14% partly due to presystemic metabolism and partly due to incomplete absorption. The elimination phase half-life is approximately 2 hours, although there is an indication of a longer terminal phase. Plasma protein binding is low (14-21%), mean volume of distribution is 170 litres.
Mean total plasma clearance is approximately 1160ml/min and the mean renal plasma clearance is approximately 260ml/min. Non-renal clearance accounts for about 80% of the total clearance. Sumatriptan is eliminated primarily by oxidative metabolism mediated by monoamine oxidase A.

Special patient populations
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 systemic exposure is almost doubled.

The pharmacokinetics in patients with severe hepatic impairment have not been studied (see Section 4.3 Contraindications and Section 4.4 Warnings and Precautions).

The major metabolite, the indole acetic acid analogue of Sumatriptan is mainly excreted in the urine, where it is present as a free acid and the glucuronide conjugate. It has no known 5HT1 or 5HT2 activity. Minor metabolites have not been identified. The pharmacokinetics of oral Sumatriptan do not appear to be significantly affected by migraine attacks.

In a pilot study, no significant differences were found in the pharmacokinetic parameters between the elderly and young healthy volunteers.