Relpax Mechanism of Action

Pharmacotherapeutic Group: Selective serotonin (5-HT₁) agonist. ATC Code: N02CC.
Pharmacology: Pharmacodynamics: Mechanism of Action: Eletriptan is a potent and selective agonist at the vascular 5-HT_1B and neuronal 5-HT_1D receptors. Eletriptan also exhibits high affinity for the 5-HT_1F receptor which may contribute to its anti-migraine mechanism of action. Eletriptan has modest affinity for the human recombinant 5-HT_1A, 5-HT_2B, 5-HT_1E and 5-HT₇ receptors.
Further Information on Clinical Trials: The efficacy and safety of eletriptan in the acute treatment of migraine has been evaluated in more than 5000 patients who received eletriptan 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.
Eletriptan was also effective in the treatment of associated symptoms of migraine such as vomiting, nausea, photophobia and phonophobia.
Eletriptan is consistently effective in migraine with or without aura and in menstrually associated migraine. Eletriptan does not help prevent migraine headache and therefore eletriptan 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 eletriptan than with normal volunteers (see Precautions). This cannot be explained by any pharmacokinetic changes and so may represent a specific pharmacodynamic response to eletriptan in patients with renal impairment.
Pharmacokinetics: Absorption: Eletriptan is rapidly and well absorbed across the gastrointestinal tract (at least 81%) after oral administration. Absolute oral bioavailability across males and females is approximately 50%. The mean T_max occurs at approximately 1.5 hours after oral dosing. Linear pharmacokinetics were demonstrated over the clinical dose range (20-80 mg).
The AUC and C_max 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 T_max 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 twice daily), the drug accumulation over 7 days was greater than predicted (approximately 40%).
Distribution: The volume of distribution of eletriptan following intravenous administration is 138 L indicating distribution into the tissues. Eletriptan is only moderately protein bound (approximately 85%).
Metabolism: 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 drug and so would not be expected to significantly contribute to the therapeutic action of eletriptan.
Elimination: Mean total plasma clearance of eletriptan following intravenous 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 (7-11 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.
Hepatic Insufficiency: 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 C_max (18%). This small change in exposure is not considered clinically relevant.
Renal Insufficiency: 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.
Toxicology: Preclinical Safety Data: Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity and toxicity to reproduction.