Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Selective Serotonin (5HT1) receptor agonists ATC code: NO2C C06 
Mechanism of action

Eletriptan is a selective agonist at the vascular 5-HT1B and neuronal 5-HT1D receptors. Eletriptan also exhibits high affinity for the 5-HT1F receptor which may contribute to its anti-migraine mechanism of action. Eletriptan has modest affinity for the human recombinant 5-HT1A, 5-HT2B, 5-HT1E and 5-HT7 receptors.

Clinical efficacy and safety

The efficacy and safety of RELERT® in the acute treatment of migraine has been evaluated in 10 placebo-controlled trials involving more than 6000 patients (in all treatment groups) at doses of 20 to 80 mg. Headache relief occurred as early as 30 minutes following oral dosing. Response rates (i.e.
reduction of moderate or severe headache pain to no or mild pain) 2 hours after dosing were 59-77% for the 80 mg dose, 54-65% for the 40 mg dose, 47-54% for the 20 mg dose, and 19-40% following placebo. RELERT® was also effective in the treatment of associated symptoms of migraine such as vomiting, nausea, photophobia and phonophobia.

The recommendation for dose titration to 80 mg, is derived from open label long term studies and from a short term double blind study, where only a trend towards statistical significance was observed.

RELERT® remains effective in menstrually associated migraine. RELERT®, if taken during the aura phase, has not been demonstrated to prevent migraine headache and therefore RELERT® should only be taken during the headache phase of migraine.

In a non placebo controlled pharmacokinetic study of patients with renal impairment, larger elevations in blood pressure were recorded after an 80 mg dose of RELERT® than with normal volunteers (see section 4.4). This cannot be explained by any pharmacokinetic changes and so may represent a specific pharmacodynamic response to eletriptan in patients with renal impairment.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
Eletriptan is rapidly and well absorbed across the gastro-intestinal tract (at least 81%) after oral administration. Absolute oral bioavailability across males and females is approximately 50%. The 
median Tmax is 1.5 hours after oral dosing. Linear pharmacokinetics were demonstrated over the clinical dose range (20-80 mg).

The AUC and Cmax of eletriptan were increased by approximately 20-30% following oral administration with a high fat meal. Following oral administration during a migraine attack, there was a reduction of approximately 30% in AUC and Tmax was increased to 2.8 hours.

Following repeated doses (20 mg three times daily) for 5-7 days, the pharmacokinetics of eletriptan remained linear and accumulation was predictable. On multiple dosing of larger doses (40 mg three times daily and 80 mg two times daily), the accumulation of eletriptan over 7 days was greater than predicted (approximately 40%).

Distribution

The volume of distribution of eletriptan following IV administration is 138L indicating distribution into the tissues. Eletriptan is only moderately protein bound (approximately 85%).

Biotransformation

In vitro studies indicate that eletriptan is primarily metabolised by hepatic cytochrome P-450 enzyme CYP3A4. This finding is substantiated by increased plasma concentrations of eletriptan following co-administration with erythromycin and ketoconazole, known selective and potent CYP3A4 inhibitors. In vitro studies also indicate a small involvement of CYP2D6 although clinical studies do not indicate any evidence of polymorphism with this enzyme.

There are two major circulating metabolites identified that significantly contribute to plasma radioactivity following administration of C14-labelled eletriptan. The metabolite formed by N-oxidation, has demonstrated no activity in animal in vitro models. The metabolite formed by N-demethylation, has been demonstrated to have similar activity to eletriptan in animal in vitro models. A third area of radioactivity in plasma has not been formally identified, but is most likely to be a mixture of hydroxylated metabolites which have also been observed excreted in urine and faeces.

The plasma concentrations of the N-demethylated active metabolite are only 10-20% of those of parent and so would not be expected to significantly contribute to the therapeutic action of eletriptan.

Elimination

Mean total plasma clearance of eletriptan following IV administration is 36 L/h with a resultant plasma half-life of approximately 4 hours. The mean renal clearance following oral administration is approximately 3.9 L/h. Non-renal clearance accounts for approximately 90% of the total clearance indicating that eletriptan is eliminated primarily by metabolism.

Pharmacokinetics in Special Patient Groups

Gender
A meta analysis across clinical pharmacology studies and a population pharmacokinetic analysis of clinical trial data indicate that gender does not have any clinically significant influence on plasma concentrations of eletriptan.

Elderly (over 65 years of age)

Though not statistically significant, there is a small reduction (16%) in clearance associated with a statistically significant increased half-life (from approximately 4.4 hours to 5.7 hours) between elderly (65-93 years) and younger adult subjects.

Adolescents (12-17 years of age)

The pharmacokinetics of eletriptan (40 mg and 80 mg) in adolescent migraine patients dosed between attacks, were similar to those seen in healthy adults.

Children (6-11 years of age)

The clearance of eletriptan is unchanged in children relative to adolescents. However the volume of distribution is lower in children resulting in higher plasma levels than would be predicted following the same dose in adults.

Patients with hepatic impairment

Subjects with hepatic impairment (Child-Pugh A and B) demonstrated a statistically significant increase in both AUC (34%) and half-life. There was a small increase in Cmax (18%). This small change in exposure is not considered clinically relevant.

Patients with renal impairment

Subjects with mild (creatinine clearance 61-89 ml/min), moderate (creatinine clearance 31-60 ml/min) or severe (creatinine clearance <30 ml/min) renal impairment did not have any statistically significant alterations in their eletriptan pharmacokinetics or plasma protein binding. Blood pressure elevations were observed in this group.