Almotriptan

Almotriptan is a selective 5-HT_1B and 5-HT_1D receptor agonist. These receptors mediate vasoconstriction of certain cranial vessels, as demonstrated in studies using isolated human tissue preparations. Almotriptan also interacts with the trigeminovascular system, inhibiting extravasation of plasma proteins from dural vessels following trigeminal ganglionic stimulation, which is a feature of neuronic inflammation that seems to be involved in the physiopathology of migraine. Almotriptan has no significant activity on other 5-HT receptor subtypes and no significant affinity for adrenergic, adenosine, angiotensin, dopamine, endothelin or tachykinin binding sites.

Pharmacodynamic effects

The efficacy of almotriptan in the acute treatment of migraine attacks was established in four multicentre, placebo-controlled clinical trials including more than 700 patients who were administered 12.5 mg. The decrease in pain began 30 minutes after administration, and the percentage of response (reduction of headache from moderate-severe to mild or absent) after 2 hours was 57-70% with almotriptan and 32-42% after placebo. In addition, almotriptan relieved nausea, photophobia and phonophobia associated with migraine attacks.

Almotriptan is well absorbed, with an oral bioavailability of about 70%. Maximum plasma concentrations (C_max) occur approximately between 1.5 and 3.0 hours after administration. The rate and extent of absorption is unaffected by concomitant ingestion of food. In healthy subjects administered single oral doses ranging from 5 mg to 200 mg, C_max and AUC were proportional to dose, indicating linear pharmacokinetic behaviour. The elimination half-life (t1/2) is about 3.5 h in healthy subjects. There is no evidence of any gender-related effect on the pharmacokinetics of almotriptan.

More than 75% of the dose administered is eliminated in urine, and the remainder in faeces. Approximately, the 50% of the urinary and faecal excretion is unchanged almotriptan. The major biotransformation route is via monoamine oxidase (MAO-A) mediated oxidative deamination to the indole acetic metabolite. Cytochrome P450 (3A4 and 2D6 isozymes) and flavin mono-oxygenase are other enzymes involved in the metabolism of almotriptan. None of the metabolites is significantly active pharmacologically.

After an intravenous dose of almotriptan administered to healthy volunteers the average values for the distribution volume, total clearance and elimination half-life were 195 L, 40 L/h and 3.4 h respectively. Renal clearance (CLR) accounted for about two-thirds of total clearance and renal tubular secretion is probably also involved. The CLR correlates well with renal function in patients with mild (creatinine clearance: 60-90 ml/min), moderate (creatinine clearance: 30-59 ml/min) and severe (creatinine clearance: < 30 ml/min) renal impairment. The increase of the mean t_1/2 (up to 7 hours) is statistically and clinically significant in the case of patients with severe renal impairment only. Compared with healthy subjects, the increase in the maximum plasma concentration (Cmax) of almotriptan was 9%, 84% and 72% respectively for patients with slight, moderate and severe renal impairment, whereas the increase in exposure (AUC) was 23%, 80% and 195% respectively. According to these results, the reduction of the total clearance of almotriptan was -20%, -40% and -65% respectively for patients with slight, moderate and severe renal impairment. As expected, total (CL) and renal (CLR) clearances were reduced but without clinical relevance in healthy elderly volunteers compared with a young control group.

Based on the mechanisms of almotriptan clearance in man, approximately 45% of almotriptan elimination appears to be due to hepatic metabolism. Therefore, even if these clearance mechanisms were totally blocked or impaired, plasma almotriptan levels would be increased a maximum of two-fold over the control state, assuming that renal function (and almotriptan renal clearance) are not altered by hepatic impairment. In patients with severe renal impairment, C_max is increased twofold, and AUC is increased approximately threefold relative to healthy volunteers. Maximal changes in pharmacokinetic parameters in patients with significant hepatic impairment would not exceed these ranges. For this reason, no study of the pharmacokinetics of almotriptan in patients with hepatic impairment was performed.

In safety pharmacology, repeated dose toxicity and reproduction toxicity studies, adverse effects were observed only at exposures well above the maximum human exposure.

Almotriptan did not show any mutagenic activity in a standard battery of in vitro and in vivo genotoxicity studies, and no carcinogenic potential was revealed in studies conducted in mice and rats.

As occurs with other 5-HT1B/1D receptor agonists, almotriptan binds to melanin. However, no ocular adverse effects associated with the drug have been observed in dogs after treatment for up to one year.