Cephalalgia

Zolmitriptan (Zomig™ formerly 311C90) is a novel 5-hydroxytryptamine (5HT)1B/1D receptor agonist with proven efficacy in the acute treatment of migraine with or without preceding aura. The drug differs from presently available members of this drug class in that it combines 5HT1B/1D receptor partial agonist activity with robust oral pharmacokinetics and an ability to inhibit trigeminovascular activation centrally as well as peripherally in preclinical studies. Consistent with its selectivity for 5HT1B/1D receptors, zolmitriptan produces constriction of various isolated blood vessels, most notably cranial arteries. In anaesthetized animals, these vascular effects manifest as a selective constriction of cranial arterio-venous anastomoses resulting in a redistribution of carotid arterial blood flow. This effect is produced without significant effects on heart rate, blood pressure or blood flow to the brain, heart or lungs. Zolmitriptan also inhibits trigeminal-evoked increases in cerebral blood flow in anaesthetized cats and blocks trigeminal-evoked plasma protein extravasation in the dura of guinea-pigs. These actions are consistent with a pre-junctional inhibition of neuropeptide release from perivascular afferents of the trigeminal nerve, as confirmed by independent studies showing that zolmitriptan blocks elevations of calcitonin-gene-related peptide in jugular venous blood during electrical stimulation of the trigeminal ganglion. In all of these effects, zolmitriptan is three to four times more potent than sumatriptan, but produces the same maximum response. Zolmitriptan crosses the intact blood-brain barrier to inhibit trigeminovascular activation in the brainstem. This was shown initially by the ability of the drug to block a brainstem reflex provoking vasoactive intestinal peptide release from the VIIth cranial (facial) nerve during trigeminal stimulation. Subsequent ex vivo autoradiography confirmed that intravenously injected [3H]zolmitriptan labels a discrete population of cells in the trigeminal nucleus caudalis (TNC) and nucleus tractus solitarius. Direct evidence for a central neuromodulatory effect of zolmitriptan was provided by electrophysiological experiments which clearly demonstrated that the drug inhibits the excitability of cells in the TNC after systemic administration. This novel preclinical profile not only distinguishes zolmitriptan from sumatriptan, but raises intriguing questions about the clinical relevance of a dual action. Studies to date show that zolmitriptan indeed modulates cranial sensory processing in humans, yet central side-effects are no different from sumatriptan. This property may account for the remarkable consistency in clinical efficacy observed in clinical trials.

Zolmitriptan (Zomig™, formerly 311C90) is a novel, oral, acute treatment for migraine. In healthy volunteers it is rapidly and extensively absorbed and has favorable oral bioavailability (approximately 40%) which is not affected by concomitant food intake. On average, 75% of its eventual Cmax is achieved within 1 h of dosing. Plasma concentrations are sustained for 4 to 6 h after dosing with single or multiple peaks in the plasma concentration-time profile, reflecting continued absorption down the gastrointestinal tract. The pharmacokinetics of zolmitriptan indicate dose proportionality over the dose range of 2.5 to 50 mg and there are no significant changes on multiple dosing. Zolmitriptan is cleared by metabolism followed by urinary excretion of the metabolites. There are three major metabolites, one of which, the N-desmethyl metabolite, is active as a 5HT1D agonist and has mean plasma concentrations approximately two thirds those of the parent compound. The other two metabolites, the N-oxide and indoleacetic acid, are inactive. The elimination half lives of zolmitriptan and its metabolites are similar, approximately 3 h. Zolmitriptan and its active metabolite are minimally protein bound in the plasma (approximately 25%). In migraine patients, plasma concentrations of zolmitriptan and its metabolites are lower during a migraine attack than outside an attack. In summary, the pharmacokinetics of zolmitriptan are simple, predictable and appropriate to an acute oral treatment for migraine.

Seven randomized studies in healthy volunteers have investigated interactions between zolmitriptan (Zomig™, formerly 311C90), a 5HT1B/1D agonist for acute migraine therapy, and selected drugs with which there was a possibility of interaction or a likelihood of concurrent use. Co-administration of oral dihydroergotamine, ergotamine, pizotifen, fluoxetine, paracetamol (acetaminophen)/metoclopramide or selegiline had no clinically significant effects on the pharmacokinetics of zolmitriptan or its metabolites, although small changes were observed in some cases. Co-administration of propranolol resulted in a 56% increase in the area under the plasma concentration-time curve (AUC) of zolmitriptan and a 11% decrease in the AUC of the active metabolite 183C91. However, these pharmacokinetic changes are unlikely to be relevant at lower clinical doses. Moclobemide, a monoamine oxidase A (MAO-A) inhibitor, decreased the clearance of zolmitriptan and, in particular, 183C91. This suggests that MAO-A is involved in the metabolism of 183C91 and it may be prudent to limit the daily zolmitriptan dose in migraine patients maintained on a MAO-A inhibitor. The clinically insignificant blood pressure increases produced by zolmitriptan, and the tolerability profile of this agent, were unaffected by any of the concomitant medications. Clinically significant interactions between zolmitriptan and commonly co-prescribed antimigraine therapies are unlikely.

The efficacy of zolmitriptan (Zomig™, 311C90), a 5-hydroxytryptamine (5HT)1B/1D receptor agonist, in the acute oral treatment of migraine was evaluated in an extensive clinical trial program. Four randomized, placebo-controlled studies (total 2480 patients) were performed; data from two of these trials established that a 2.5 mg dose was on the shoulder of the dose-response curve (2-h headache response rate 64%), showing similar efficacy to the 5 mg dose (67%). In this program, the efficacy of zolmitriptan was not influenced by the pretreatment headache duration; the presence of aura preceding the headache, migraine associated with menses or migraine upon awakening; or by concomitant use of oral contraceptives or antidepressants. In addition, zolmitriptan 5 mg proved consistently effective in the treatment of multiple migraine attacks for up to 1 year. Zolmitriptan reduced the incidence of nausea, photophobia and phonophobia, reduced impairment of normal activity and demonstrated positive effects on patients’ quality of life. Thus, zolmitriptan is a highly effective acute oral antimigraine therapy, with 2.5 mg providing the optimal balance between efficacy and tolerability.

Zolmitriptan (Zomig™, formerly 311C90) at doses of 0.5–50 mg was administered to 316 unique volunteers in clinical pharmacology studies and 2,750 unique patients in eight clinical studies of acute migraine treatment. Overall, subjects received almost 50,000 doses; 97% of exposures were at doses >2.5 mg. In the clinical pharmacology studies, the overall incidence of subject exposures experiencing at least one adverse event was 52% with zolmitriptan 2.5 mg (28% with placebo). In placebo-controlled studies, the overall incidence of patients with at least one adverse event was dose-dependent for zolmitriptan over the 1–15 mg dose range, e.g. 42% and 46% with 1 and 2.5 mg, respectively and 58% with 5 mg (29% with placebo). Only four serious adverse events attributable to zolmitriptan were reported. In a long-term study, during which 2,058 outpatients treated a total of 31,579 migraine attacks with either one or two zolmitriptan 5 mg doses over a period of up to 1 year, the number of attacks associated with at least one adverse event was similar after one (26%) and two (24%) doses. The majority (59%) of the adverse events reported in this study (59%) occurred within 2 h of dosing, were predominantly mild (59%) or moderate (35%) in intensity, of ≦4 h duration (58%), required no further action (94%). In placebo-controlled studies, the percentage of patients who reported severe adverse events was similar with zolmitriptan 2.5 mg (4%) and placebo (5%). The most frequently reported adverse events with zolmitriptan in the placebo-controlled clinical studies were asthenia, heaviness (other than chest or neck), dry mouth, nausea, dizziness, somnolence, paresthesia and warm sensations. The type and severity of the adverse events was not influenced by gender (although the frequency of reported adverse events was higher in females, as was the case in the placebo group), age, presence of aura prior to the attack, association of migraine with menstruation, concurrent medication, or by the addition of a second zolmitriptan dose. Zolmitriptan showed a similar tolerability profile in the long-term study, in which a low withdrawal rate due to adverse events of 8% was observed. Zolmitriptan was not associated with an increased frequency of central nervous system-related adverse events in a comparative study of sumatriptan, despite pre-clinical and neurophysiological evidence of a dual peripheral and central action of zolmitriptan. Moreover, zolmitriptan doses of 5–20 mg produced no statistically significant effects on objective assessments of psychometric function. Zolmitriptan had no clinically significant effects on blood pressure (even in patients with controlled mild to moderate hypertension or impaired renal function), ECGs (e.g. there was no evidence of ischemic events) or clinical chemistry, hematological or urinalysis measurements. In summary, zolmitriptan is well tolerated, particularly at the recommended dose of 2.5 mg. Zolmitriptan has a well-defined dose-response with 2.5 mg proving highly effective and optimizing the benefit/risk ratio of treatment. Thus, zolmitriptan is well suited as an acute oral treatment for migraine in the outpatient setting.

Zolmitriptan (Zomig™, formerly 311C90) is a novel, oral antimigraine drug that is consistently effective and well tolerated in the acute treatment of migraine headache and its associated symptoms. The purpose of this article is to review data available from pharmacological and clinical trials with zolmitriptan and to summarize the clinically relevant features that distinguish this agent. We will review the attributes desirable in a migraine drug and use this as a template for assessing zolmitriptan. Zolmitriptan provides a new oral treatment option for physicians which should help improve patient outcomes.