フロバトリプタン

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 6200(SRC), determined from a structure estimation method(2), indicates that frovatriptan is expected to be immobile in soil(SRC). An estimated pKa value of 10.6 (secondary amine)(3) indicates that frovatriptan will exist primarily as a cation in the environment. Volatilization of frovatriptan from moist soil surfaces is not expected to be an important fate process(SRC) because cations do not volatilize. Frovatriptan is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.7X10-9 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2005).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 6200(SRC), determined from a structure estimation method(2), indicates that frovatriptan is not expected to adsorb to suspended solids and sediment(SRC). An estimated pKa value of 10.6 (secondary amine)(3) indicates that frovatriptan will primarily exist in cation form in the environment. Volatilization from water surfaces is not expected(SRC) because cations do not volatilize. According to a classification scheme(4), an estimated BCF of 2(SRC), from an estimated log Kow of 1.3(5) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2005).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), frovatriptan, which has an estimated vapor pressure of 3.7X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase frovatriptan may be removed from the air by wet or dry deposition(SRC). Frovatriptan contains the indole chromophore which absorbs at wavelengths > 290 nm(3) and therefore may be susceptible to direct photolysis by sunlight(SRC).

Three distinct pharmacological actions have been implicated in the antimigraine effect of the triptans: (1) stimulation of presynaptic 5-HT_1D receptors, which serves to inhibit both dural vasodilation and inflammation; (2) direct inhibition of trigeminal nuclei cell excitability via 5-HT_1B/1D receptor agonism in the brainstem and (3) vasoconstriction of meningeal, dural, cerebral or pial vessels as a result of vascular 5-HT_1B receptor agonism.

There is no direct experience of any patient taking an overdose of Frovatriptan. The maximum single dose of frovatriptan given to male and female patients with migraine was 40 mg (16 times the clinical dose) and the maximum single dose given to healthy male subjects was 100 mg (40 times the clinical dose) without significant adverse events.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of frovatriptan can be estimated to be 6200(SRC). According to a classification scheme(2), this estimated Koc value suggests that frovatriptan is expected to be immobile in soil. An estimated pKa value of 10.6 (secondary amine)(3) indicates that frovatriptan will exist primarily as a cation in the environment and cations generally adsorb to soil and sediment more strongly than their neutral counterparts(4).

/SIGNS AND SYMPTOMS/ Cerebral hemorrhage, subarachnoid hemorrhage, stroke and other cerebrovascular events have been reported in patients treated with 5-HT1 agonists; and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. It should be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g. stroke, hemorrhage, transient ischemic attack).

/SIGNS AND SYMPTOMS/ Risk of coronary vasospasm, myocardial ischemia and/or infarction, life-threatening cardiac rhythm disturbances, and death associated with use of 5-HT1 receptor agonists. Use of frovatriptan not recommended in patients with known or suspected ischemic or vasospastic heart disease (see Cautions: Contraindications) or in patients in whom unrecognized coronary artery disease is likely (e.g., postmenopausal women, men older than 40 years of age, patients with risk factors such as hypertension, hypercholesterolemia, smoking, obesity, diabetes, family history of coronary artery disease) unless a prior cardiovascular evaluation provides satisfactory evidence that the patient does not have coronary artery disease, ischemic heart disease, or other underlying cardiovascular disease.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

frovatriptan

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

26 hours

Elimination: Intravenous administration: Approximately 26 hours.

In vitro, cytochrome P450 1A2 appears to be the principal enzyme involved in the metabolism of frovatriptan to several metabolites including hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, and several other minor metabolites. Desmethyl frovatriptan has lower affinity for 5-HT_1B/1D receptors compared to the parent compound. The N-acetyl desmethyl metabolite has no significant affinity for 5-HT receptors. The activity of the other metabolites is unknown.

In vitro, cytochrome P450 1A2 appears to be the principal enzyme involved in the metabolism of frovatriptan. Following administration of a single oral dose of radiolabeled frovatriptan 2.5 mg to healthy male and female subjects, 32% of the dose was recovered in urine and 62% in feces. Radiolabeled compounds excreted in urine were unchanged frovatriptan, hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, together with several other minor metabolites. Desmethyl frovatriptan has lower affinity for 5-HT1B/1D receptors compared to the parent compound. The N-acetyl desmethyl metabolite has no significant affinity for 5-HT receptors. The activity of the other metabolites is unknown.

In vitro, cytochrome P450 1A2 appears to be the principal enzyme involved in the metabolism of frovatriptan to several metabolites including hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, and several other minor metabolites. Desmethyl frovatriptan has lower affinity for 5-HT_1B/1D receptors compared to the parent compound. The N-acetyl desmethyl metabolite has no significant affinity for 5-HT receptors. The activity of the other metabolites is unknown. Route of Elimination: Radiolabeled compounds excreted in urine were unchanged frovatriptan, hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, together with several other minor metabolites. Less than 10% of frovatriptan was excreted in urine after an oral dose. Half Life: 26 hours

H82Q2D5WA7

FROVATRIPTAN

Mechanisms of Action [MoA] - Serotonin 1b Receptor Agonists

Mechanisms of Action [MoA] - Serotonin 1d Receptor Agonists

Established Pharmacologic Class [EPC] - Serotonin-1b and Serotonin-1d Receptor Agonist

Frovatriptan is a Serotonin-1b and Serotonin-1d Receptor Agonist. The mechanism of action of frovatriptan is as a Serotonin 1b Receptor Agonist and Serotonin 1d Receptor Agonist.

Frovatriptan is rapidly absorbed from the duodenum, but has low oral bioavailability.

Radiolabeled compounds excreted in urine were unchanged frovatriptan, hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, together with several other minor metabolites. Less than 10% of frovatriptan was excreted in urine after an oral dose.

4.2 L/kg [males]

220 mL/min [male receiving IV dose of 0.8 mg]

Protein binding: Low (approximately 15%) to serum proteins.

Volume of distribution (VolD): Steady state : 4.2 L/kg in males and 3.0 L/kg in females.