NEW DRUG

DEVELOPMENTS SUMATRIPI'AN: A SELECTIVE 5-HYDROXYTRYPTAMINE RECEPrOR AGONIST FOR THEACUTE TREATMENT OF MIGRAINE Terence Fullerton and Fran M. Gengo

OBJECllVE: The clinicalpharmacology, pharmacokinetics, clinical efficacy,adverseeffects,and associated drug interactions of the novel antimigraine drug sumatriptan are reviewed. DATA SOURCES: English-language publications pertainingto sumatriptan were identified via a search of the MEDLINEcomputerizeddatabase. STUDY SELECllON: Open and controlledclinicalstudieswere reviewedin assessingclinicalefficacy,althoughonly the resultsof controlled, randomized trialsform the basis for the conclusions pertaining to the effectiveness of sumatriptan. DATA EXTRACllON: The primarymeasure of drug effectiveness in all clinicalstudieswas significant improvementin headacheseverity scores.Secondarymeasuresincludedfunctional ability,time to relief,rescuemedicationuse, associated symptomsof nausea! vomitingand photo/phonophobia, and, in some studies,headache recurrence rate.These data were obtainedfrom each published clinicaltrial and used in the overall analysisof sumatriptan efficacy. DATA SYNTHESIS: Sumatriptan is a serotoninagonist that has been studiedfor the acute treatmentof migraineand clusterheadache. The drug appearsto work via specificserotonin receptorsto mediate selective vasoconstriction withinthe cranialvasculature and to preventthe releaseof inflammatory mediatorsfrom trigeminal nerve terminals. The recommended dose of sumatriptan is 6 mg given subcutaneously at the onset of headache; an oral formulation is under investigation. In the publishedclinicaltrialsof the oral and subcutaneous dosage forms to date, sumatriptan was effectivein reducingheadacheseverityfrom moderate/severe to mild/absent in approximately 70-4mpercentof patientstreatedwith activedrug, comparedwith only 20-30 percentin the placebogroups,and 48 percentin the oral ergotaminetartrate/caffeine (Cafergot)-treated group. Secondarymeasuresof effectiveness also favored sumatriptan. There may be a higher rate of headacherecurrence with sumatriptan comparedwith placeboor Cafergot,althoughfurther study is necessary to confirm this observation. Adverseeffects

TERENCE FULLERTON, Phann. D., BCPS, is a Clinical Research Fellow in Neurophannacology and Pharmacokinetics, Center for Clinical Phannacy Research, School of Pharmacy, State University of New York (SUNY) at Buffalo, and Division of Neurophannacology, The Dent Neurologic Institute, Millard Fillmore Hospital; and FRAN M. GENGO, Phann.D., FCP, is the Director, Division of Neuropharmacology, Dent Neurologic Institute, and an Associate Professor of Pharmacy and Neurology, Schools of Pharmacy and Medicine, SUNY at Buffalo, Buffalo, NY. Reprints: Fran M. Gengo, Phann.D., FCP, Division of Neurophannacology, Dent Neurologic Institute, Millard Fillmore Hospital, 3 Gates Cir., Buffalo, NY 14209. Sumatriptan (Imitrex), Glaxo.

Thisarticle is approved forcontinuing education credit

Sumatriptan (GR43175) HO

Figure I. Graphic formulas of sumatriptan (GR43175) and serotonin (5-hydroxytryptamine, 5-HT). Adapted from Reference 4.

associated with sumatriptan administration generally were mild and transientand includedtingling, warm/hotsensations, and pressure and tightness in the chest and neck. No significant drug interactions have yet been identified. CONCLUSIONS: Sumatriptan appearsto representa safe and effective alternative to the ergot alkaloids for the abortivetreatmentof acute migraine. However,furtherclinicaltrials,especially those yielding comparative data with currentantimigraine agents,are neededto determinethe full therapeutic contribution of sumatriptan.

Ann Pharmacother 1992;26:800-8. IN 1988, the International Headache Society's Headache Classification Committee revised the definition of migraine as an "idiopathic, recurring headache disorder manifesting in attacks lasting 4 to 72 hours. Typical characteristics of the headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, and association with nausea, vomiting, photo- and phonophobia."! Recent data suggest that migraine afflicts approximately 17.6 percent of women and 5.7 percent of men in the US population. Projections suggest that more than 23 million individuals are plagued by migraine, and 8.7 million females and 2.6 million males suffer from headaches that cause moderate to severe disability. Thus, it appears to be a significant malady in both males and females, although, depending on age, migraine is approximately two to three times more common in fe-

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males. The data set forth by Stewart et al. also report a significantly higher prevalence in lower socioeconomic groups than in subsets with higher household income, suggesting a possible association between migraine-associated disability and impairment of work- or school-related performance, leading to downward socioeconomic mobility.' Thus, migraine must be viewed as a major cause of morbidity in the adult working population of the US. Treatment of migraine traditionally has focused on abortive therapy for patients with less than two attacks per month, and prophylactic plus abortive therapy in people with more frequent headaches. Acute treatment of migraine relies heavily upon the use of ergotamine-containing preparations, and to a lesser extent, on nonsteroidal antiinflammatory drugs (NSAIDs). Narcotic analgesics and injectable dihydroergotamine (DHE) are the mainstay for the management of headache pain in severe cases. Abortive agents, especially ergotamine, have significant adverse effects that limit their usefulness, and are often ineffective unless administered early in the attack. Thus, newer abortive therapies, if safe and effective, would be significant additions to currently available treatments for vascular headaches. Sumatriptan is a novel agent marketed in some European countries for the abortive therapy of migraine and its subcutaneous formulation is currently pending approval in the US. As an oral form of sumatriptan is currently under investigation, data on both routes of administration are reviewed. Pharmacology The mechanisms by which sumatriptan exerts its pharmacologic effect are not defmitively established. To appreciate the proposed mechanisms of sumatriptan's pharmacologic effect, one must be familiar with some of the most common theories pertaining to migraine pathophysiology. Although it has been long debated, the most familiar premise involves four general dynamic events within the cranial vasculature: (1) initial vasoconstriction of cerebral vessels; (2) the reactive vasodilatation of intracranial and scalp vessels, which causes migraine pain; (3) extravasation of plasma protein into the dura mater; and (4) a secondary muscle contraction often resulting in concomitant underlying tension-type headache.' A plethora of neurotransmitter and neurohormonal factors have been implicated as triggering the evolution of migraine; however, serotonin (5-hydroxytryptamine [5-HT]) receptor mechanisms have received considerable attention in recent years.v Indeed, administration of exogenous 5HT has been shown to ameliorate attacks.v' It is unclear, however, whether this beneficial effect results from replenishment of peripheral and central5-HT stores in a relative state of deficiency, or to a direct vasoconstrictive effect upon cranial vessels.' This information, plus the observation that many of the currently used agents for migraine abortion and prophylaxis have significant activities at 5HT receptors, led to the development of new compounds that act primarily within the serotonergic system. Sumatriptan is structurally related to 5-HT (Figure 1). However, its activity appears to be limited to the 5-HT.like receptor subtype, which is thought to preside predominantly within the vasculature of certain cranial vessels." Acting as an agonist at these receptors, sumatriptan has

been shown to cause increases in petfusion pressure in isolated human dura mater.' These data are reflective of selective vasoconstriction within the meningeal circulation, and this pharmacodynamic effect occurs in a concentration-dependent fashion. Because sumatriptan does not appear to traverse the blood-brain barrier (BBB),4 it has been proposed that the drug primarily acts upon 5-HT clike receptors within cranial vessels that lack a BBB, such as the large conducting arteries and vessels within the meningeal circulation." This contention is also supported by sumatriptan's lack of effect on cerebral blood flow." Constriction of only these large intracranial arteries by sumatriptan would not be expected to diminish cerebral blood flow, as these are not resistance vessels and do not regulate cerebral blood flow." Sumatriptan, unlike the ergot alkaloids, has little activity at other amine receptors, such as 5-HT2 and 5-HT3 - , dopamine.-, and beta-, alpha.-, and alphaj-receptors. S,I2,13 This lack of activity at non-c-Hlj-like sites may explain the relative absence of adverse effects, such as peripheral vasoconstriction and nausea and vomiting commonly associated with ergotamine administration. Humphrey and Feniuk shed further light on the possible mechanisms of action of sumatriptan. As discussed above, the pain of migraine is believed to arise from the dilatation and distension of the large intracranial vessels and meningeal arteries. The events leading to the migraine attack may involve stimulation of the trigeminal nerve by an array of precipitating factors, and release of vasoactive peptides such as calcitonin gene-related peptide and substance P from the nerve terminals within the cerebral vasculature. These mediators, as well as prostaglandins and bradykinin, may cause extravasation of plasma proteins, producing a sterile inflammatory process and vessel distension. Pain probably results from direct stimulation of sensory nerve terminals by protein extravasation, and the increased transmural pressure caused by vasodilatation." Sumatriptan has been shown to reduce the extravasation of plasma proteins into the perivascular space caused by trigeminal nerve stimulation, thereby documenting a mechanism by which the sterile arteritis that accompanies migraine is minimized." This antiinflammatory action of sumatriptan may result from direct inhibition of vasoactive peptide release from trigeminal nerve terminals, via activation of 5-HTI-like autoreceptors, or may, in part, be an indirect consequence of primary vasoconstriction. Sumatriptan does not appear to affect afferent nerve transmission, nor does it exhibit any direct analgesic activity.' In all likelihood, both its ability to cause vasoconstriction and proclivity for preventing the release of inflammatory mediators from trigeminal nerve terminals are important in the overall antirnigraine activity of sumatriptan. The proposed mechanisms of action of sumatriptan are summarized in Figure 2. Pharmacokinetics There is only one publication that contains information on the pharmacokinetics of sumatriptan. This review pools the pharmacokinetic data from a total of 655 subjects. 15 Various routes of administration of sumatriptan have been studied, including oral, intravenous, subcutaneous, intramuscular, sublingual, intranasal, and rectal administration. Pharmacokinetic data are available for the oral, intrave-

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nous, and subcutaneous routes only. These data are summarized in Table 1. ABSORPTION

Sumatriptan is absorbed rapidly and completely upon subcutaneous administration, with a mean time to reach maximum concentration (Tmax) of ten minutes, and maximum serum concentration (C max) of 74.2 ng/mL after a recommended 6-mg dose. Absolute bioavailability averaged 96 percent. Data stratified by injection site are not available, although the drug was effective when given subcutaneously over the deltoid as well as the thigh, suggesting that sumatriptan is well absorbed from both sites. IM 7 After a lOO-mg oral dose (uncoated tablet), mean peak concentrations of 53.8 ng/mL result at approximately 1.5 hours, although C max and Tmax values are highly variable. Interestingly, sumatriptan often exhibits multiple peaks in plasma concentrations after oral dosing. Reasons for these fmdings have not been addressed, but may suggest that the drug undergoes active enterohepatic cycling. Bioavailability is poor after oral administration, with approximately 15 percent of the dose reaching the systemic circulation. Because only about 10 percent of an oral dose was recovered in the feces, as determined by radiolabeling studies, it is likely that sumatriptan's poor bioavailability is largely attributable to extensive presystemic clearance on first pass. Studies examining the absorption of sumatriptan during

nocicep#ve

impulses bfocked

trigeminal nerve

the migrainous state show no difference in pharmacokinetics compared with the nonmigrainous condition. IS Similarly, there appear to be no significant differences in kinetic parameters between the fed and fasted states. IS DISTRIBUTION

The mean apparent volume of distribution of sumatriptan is 170 L, or approximately 2.4 L/kg based on an average body weight of 70 kg, suggesting a large degree of tissue binding. Plasma protein binding is low (14-21 percent) over the studied concentration range of 10-100 ng/mL. IS Single doses of sumatriptan do not appear to result in significant amounts of drug traversing the BBB, as evident from radioligand binding studies performed in rodents.' METABOLISM AND ELIMINAnON

Sumatriptan is predominantly metabolized, with approximately only 20 percent of a subcutaneous dose recovered in the urine as the parent compound. The drug's phase I metabolite is an indole acetic acid analog, which, consistent with high first-pass metabolism, reaches plasma concentrations six to seven times that of the parent compound after oral administration. This metabolite has no significant serotonergic activity. IS The total plasma clearance of sumatriptan is approximately 1200 mL/min, with renal clearance equaling 260 mL/min, indicating that sumatriptan is probably actively secreted in the renal tubules. The mean half-life (t l/2) is 2 hours, this value representing the most dominant elimination rate for all routes of drug administration. However, a terminal t l/ 2 of approximately 7 hours was observed after oral dosing, and occurred roughly 12 hours after administration." This observation again suggests that enterohepatic cycling may be prolonging the residence time of sumatriptan. This terminal t l/2 contributed relatively little to the overall disposition of the drug. Values for clearance and t l/2 are in close agreement with measurements obtained in an early healthy volunteer study of six subjects."

vessel diameter normalized

vascular

smooth muscle

Clinical Studies

NORMAL

SUMATRIPTAN

MIGRAINE

Figure 2. Hypothetical mechanism of action of sumatriptan. During a migrainous headache. intracranial blood vessels may become distended and edematous secondary to activation of the trigeminal nerve terminals and the subsequent release of neuropeptides. Sumatriptan activates vascular 5-HT t receptors to constrict the affected vessels. thereby opposing the extravasation and consequent pain. An additional inhibitory action on the sensory nerve terminals could concomitantly lead to a reduction in the release of neuropeptides. Adapted from Reference 12, with permission.

Table 1. Pharmacokinetic Parameters of Oral and Subcutaneous Sumatriptan" PHARMACOKINETIC PARAMETER

Absolute bioavailability (%) subcutaneous oral Total plasma clearance" (mL/min) Renal plasma clearance" (mL/min) Volume of distribution (L) Plasma t l/2 (h) Terminal t l/2b (h) "Adapted from Reference 15. bOrai formulation. t l/2 = half-life.

MEAN

96 14 1200 260

170 2 7

RANGE

68-134 10-26 640-1600

140-470 90-320 1-4 4-26

MIGRAINE

Nearly all of the recent published clinical studies have evaluated sumatriptan for use in the abortive therapy of migraine. These studies are outlined in Table 2.16,17,20-25 The methodologies employed in all of the clinical trials were similar and are reviewed extensively elsewhere." All were double-blind, placebo-controlled, or comparative, and carried out using parallel groups. Primary therapeutic endpoints were based upon subjective assessment of headache severity before and after treatment. The evaluations of headache intensity were performed using a simple fourpoint scale as follows: 0 = no headache, 1 = mild headache, 2 =moderate headache, and 3 =severe headache. A headache score of 2 or 3 enabled the subject to participate in the study, and in all cases successful treatment was defined as improvement in headache scores from pretreatment values to either 0 or 1. Subgroup analysis often was performed to explore the effects of gender, migraine type, prophylactic medication, and, most notably, time since headache onset. Some of the major clinical trials also evaluated the functional ability of the patient before and after

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Sumatriptan

treatment, using a similar rating scale as for headache pain, which ranged from a score of 0 (functioning normally) to 3 (requiring complete bedrest). Secondary measures of therapeutic effect included the need for and amount of rescue medication during attacks; time to onset of headache improvement; relief of concomitant symptoms such as photophobia and phonophobia, and nausea and vomiting; and headache recurrence. The patient's overall opinion of treatment was also evaluated in most trials. As discussed previously, sumatriptan has been administered by virtually every route. Early open studies noted marked relief from headache symptoms in the majority of patients receiving sumatriptan and established the initial dosage ranges of oral and parenteral sumatriptan in migraine.":" Because of a significant placebo effect noted in trials of acute migraine treatment, the early open studies were not useful in assessing the effectiveness of sumatriptan. These uncontrolled studies were followed by the later controlled clinical trials listed in Table 2. These placebocontrolled and comparative studies most often evaluated sumatriptan dosed by oral or subcutaneous routes, although in one trial the drug was administered intranasally.'" The results of these latter investigations form the basis for the conclusions regarding the efficacy of sumatriptan. Two large European trials studied oral sumatriptan for the abortive therapy of migraine. The first of these was a dose-ranging study that examined three doses of sumatriptan and placebo. Patients (n=1130) were randomized to receive 100 mg, 200 mg, 300 mg, or placebo as outpatients for up to three separate attacks. Measures of therapeutic response were obtained by data collected in patient diaries,

with information pertaining to the first attack used in the primary analysis of efficacy. All doses of sumatriptan were significantly superior to placebo across all parameters of effectiveness (p