Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Accord-UK Ltd (Trading style: Accord), Whiddon Valley, Barnstaple, Devon, EX32 8NS
Pharmacotherapeutic group: Selective serotonine (5HT1) agonists
ATC code: N02CC03
Zolmitriptan has been demonstrated to be a selective agonist for 5HT1B/1D receptors mediating vascular contraction. Zolmitriptan has high affinity for human recombinant 5HTIB and 5HTID receptors, and modest affinity for 5HTIA receptors. Zolmitriptan has no significant affinity or pharmacological activity at other 5HT receptor subtypes (5HT2, 5HT3, 5HT4) or adrenergic, histaminic, muscarinic or dopaminergic receptors.
In animal models, the administration of zolmitriptan causes vasoconstriction in the carotid arterial circulation. In addition, experimental studies in animals suggest that zolmitriptan inhibits central and peripheral trigeminal nerve activity with inhibition of neuropeptide release (calcitonin gene related peptide (CGRP), vasoactive intestinal peptide (VIP) and Substance P).
In clinical studies with zolmitriptan conventional tablets the onset of efficacy is apparent from one hour, with increasing efficacy being noted between 2 and 4 hours on headache and other symptoms of migraine such as nausea, photophobia and phonophobia.
Zolmitriptan, when administered as conventional oral tablets, is consistently effective in migraine with or without aura and in menstrually associated migraine. Zolmitriptan, when administered as conventional oral tablets, if taken during the aura, has not been demonstrated to prevent the migraine headache and therefore Zolmitriptan 2.5mg Orodispersible Tablets should be taken during the headache phase of migraine.
One controlled clinical trial in 696 adolescents with migraine failed to demonstrate superiority of zolmitriptan tablets at doses of 2.5 mg, 5 mg and 10 mg over placebo. Efficacy was not demonstrated.
Following oral administration of zolmitriptan conventional tablets, zolmitriptan is rapidly and well absorbed (at least 64%) after oral administration to man. The mean absolute bioavailability of the parent compound is approximately 40%. There is an active metabolite (the N-desmethyl metabolite) which is also a 5HT1B/1D receptor agonist and is 2 to 6 times as potent, in animal models, as zolmitriptan.
In healthy subjects, when given as a single dose, zolmitriptan and its active metabolite, the N-desmethyl metabolite , display dose-proportional AUC and Cmax over the dose range 2.5 to 50mg. Absorption of zolmitriptan is rapid. In healthy volunteers, 75% of Cmax is achived within 1 hour, and after this the concentration of zolmitriptan in plasma is maintained at approximately this level until 4-5 hours after dosing.
Zolmitriptan absorption is unaffected by the presence of food. There was no evidence of accumulation on multiple dosing of zolmitriptan.
Plasma concentration of zolmitriptan and its metabolites are lower in the first 4 hours after drug administration during a migraine compared with a migraine-free period, suggesting delayed absorption consistent with the reduced rate of gastric emptying observed during a migraine attack.
Zolmitriptan orodispersible tablet was demonstrated to be bioequivalent with the conventional tablet in terms of AUC and Cmax for zolmitriptan and its active metabolite 183C91. Clinical pharmacology data show that the tmax for zolmitriptan can be later for the orally dispersible tablet (range 0.6 to 5h, median 3h) compared to the conventional tablet (range 0.5 to 3h, median 1.5h). The tmax for the active metabolite was similar for both formulations (median 3h).
Zolmitriptan is eliminated largely by hepatic biotransformation followed by urinary excretion of the metabolites. There are three major metabolites: the indole acetic acid, (the major metabolite in plasma and urine), the N-oxide and N-desmethyl analogues. The N-desmethylated metabolite is active whilst the others are not. Plasma concentrations of the N-desmethylated metabolite are approximately half those of the parent drug, hence it would therefore be expected to contribute to the therapeutic action of zolmitriptan. Over 60% of a single oral dose is excreted in the urine (mainly as the indole acetic acid metabolite) and about 30% in faeces mainly as unchanged parent compound. Following intravenous administration, the mean total plasma clearance is approximately 10 ml/min/kg, of which one quarter is renal clearance. Renal clearance is greater than glomerular filtration rate suggesting renal tubular secretion. The volume of distribution following intravenous administration is 2.4 L/kg. Plasma protein binding of zolmitriptan and the N-desmethyl metabolite is low (approximately 25%). The mean elimination half-life of zolmitriptan is 2.5 to 3 hours. The half-lives of its metabolites are similar, suggesting their elimination is formation-rate limited.
Renal clearance of zolmitriptan and all its metabolites is reduced (7-8 fold) in patients with moderate to severe renal impairment compared to healthy subjects, although the AUC of the parent compound and the active metabolite were only slightly higher (16 and 35% respectively) with a 1 hour increase in half-life to 3 to 3.5 hours. These parameters are within the ranges seen in healthy volunteers.
The metabolism of zolmitriptan is reduced in hepatic impairment in proportion to the extent of the impairment. Zolmitriptan AUC and Cmax were increased by 226% and 50%, respectively and the half life was prolonged to 12 h in subjects with severe liver disease compared to healthy subjects. Exposure to the metabolites, including the active metabolite was reduced.
The pharmacokinetics of zolmitriptan in healthy elderly subjects were similar to those in healthy young volunteers.
Preclinical effects in single and repeat dose toxicity studies were observed only at exposures well in excess of the maximum human exposure.
The findings from in vitro and in vivo genetic toxicity studies show that genotoxic effects of zolmitriptan are not to be expected under the conditions of clinical use.
No tumours relevant to the clinical use were found in mouse and rat carcinogenicity studies.
As with other 5HT1B/1D receptor agonists, zolmitriptan binds to melanin.
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