Frovatriptan

Frovatriptan is a selective agonist for 5-HT receptors, which shows high affinity for 5-HT_1B and 5-HT_1D binding sites in radioligand assays and exhibits potent agonist effects at 5-HT_1B and 5-HT_1D receptors in functional bioassays. It exhibits marked selectivity for 5-HT_1B/1D receptors and has no significant affinity for 5-HT₂, 5-HT₃, 5-HT₄, 5-HT₆, α-adrenoreceptors, or histamine receptors. Frovatriptan has no significant affinity for benzodiazepine binding sites.

Frovatriptan is believed to act selectively on extracerebral, intracranial arteries to inhibit the excessive dilatation of these vessels in migraine. At clinically relevant concentrations, frovatriptan produced constriction of human isolated cerebral arteries with little or no effect on isolated human coronary arteries.

Absorption

After administration of a single oral 2.5 mg dose to healthy subjects, the mean maximum blood concentration of frovatriptan (C_max), reached between 2 and 4 hours, was 4.2 ng/mL in males and 7.0 ng/mL in females. The mean area under the curve (AUC) was 42.9 and 94.0 ng.h/mL for males and females respectively.

The oral bioavailability was 22% in males and 30% in females. The pharmacokinetics of frovatriptan were similar between healthy subjects and migraine patients and there was no difference in pharmacokinetic parameters in the patients during a migraine attack or between attacks.

Frovatriptan displayed generally linear pharmacokinetics over the dose range used in clinical studies (1 mg to 40 mg).

Food had no significant effect on the bioavailability of frovatriptan, but delayed t_max slightly by approximately 1 hour.

Distribution

The steady state volume of distribution of frovatriptan following intravenous administration of 0.8 mg was 4.2 L/kg in males and 3.0 L/kg in females.

Binding of frovatriptan to serum proteins was low (approximately 15%). Reversible binding to blood cells at steady state was approximately 60% with no difference between males and females. The blood:plasma ratio was about 2:1 at equilibrium.

Biotransformation

Following oral administration of radiolabelled frovatriptan 2.5 mg to healthy male subjects, 32% of the dose was recovered in urine and 62% in faeces. Radiolabelled compounds excreted in urine were unchanged frovatriptan, hydroxy frovatriptan, N-acetyl desmethyl frovatriptan, hydroxy N-acetyl desmethyl frovatriptan, and desmethyl frovatriptan, together with several other minor metabolites. Desmethyl frovatriptan had about 3-fold lower affinity at 5-HT1 receptors than the parent compound. N-acetyl desmethyl frovatriptan had negligible affinity at 5-HT1 receptors. The activity of other metabolites has not been studied.

The results of in vitro studies have provided strong evidence that CYP1A2 is the cytochrome P450 isoenzyme primarily involved in the metabolism of frovatriptan. Frovatriptan does not inhibit or induce CYP1A2 in vitro.

Frovatriptan is not an inhibitor of human monoamine oxidase (MAO) enzymes or cytochrome P450 isozymes and therefore has little potential for drug-drug interactions. Frovatriptan is not a substrate for MAO.

Elimination

The elimination of frovatriptan is biphasic with a distribution phase prevailing between 2 and 6 hours. Mean systemic clearance was 216 and 132 mL/min in males and females, respectively. Renal clearance accounted for 38% (82 mL/min) and 49% (65 mL/min) of total clearance in males and females, respectively. The terminal elimination half-life is approximately 26 hours, irrespective of the sex of the subjects, however the terminal elimination phase only becomes dominant after about 12 hours.

Gender

AUC and C_max values for frovatriptan are lower (by approximately 50%) in males than in females. This is due, at least in part, to the concomitant use of oral contraceptives. Based on the efficacy or safety of the 2.5 mg dose in clinical use, dosage adjustment with respect to gender is not necessary.

Elderly

In healthy elderly subjects (65 to 77 years) AUC is increased by 73% in males and by 22% in females, compared to younger subjects (18 to 37 years). There was no difference in t_max or t_1/2 between the two populations.

Renal impairment

Systemic exposure to frovatriptan and its t_1/2 were not significantly different in male and female subjects with renal impairment (creatinine clearance 16 – 73 mL/min), compared to that in healthy subjects.

Hepatic impairment

Following oral administration in male and female subjects aged 44 to 57, with mild or moderate hepatic impairment (Child-Pugh grades A and B), mean blood concentrations of frovatriptan were within the range observed in healthy young and elderly subjects. There is no pharmacokinetic or clinical experience with frovatriptan in subjects with severe hepatic impairment.

During toxicity studies after single or repeated administration, preclinical effects were only observed at exposure levels in excess of the maximum exposure level in man.

Standard genotoxicity studies did not reveal a clinically relevant genotoxic potential of frovatriptan.

Frovatriptan was foetotoxic in rats, but in rabbits foetotoxicity was observed only at maternally toxic dose levels.

Frovatriptan was not potentially carcinogenic in standard rodent carcinogenicity studies and in p53 (+/-) mouse studies at exposures considerably higher than anticipated in humans.