A brief account of the pharmacology of sumatriptan is as follows:
Pharmacodynamics. This is a selective agonist of serotonin 5-HT1-like receptors including 5-HT1B/1D subtypes. The drug has no significant activity at 5-HT2 or 5-HT3 receptors or at dopamine, gamma-aminobutyric acid, or adrenoreceptors. Sumatriptan causes vasoconstriction of large cerebral blood vessels, particularly when they are dilated during an acute migraine attack. It can also cause constriction of peripheral and coronary arteries. It blocks neurogenic protein extravasation within the trigeminovascular system and attenuates increased calcitonin gene-related peptide levels in patients with migraine. A randomized, double-blind, placebo-controlled, crossover study in healthy adults showed that forehead dermal blood flow responses to capsaicin, most likely induced by the release of calcitonin gene-related peptide, were attenuated by sumatriptan (11). This model is a biomarker of trigeminovascular effects of antimigraine drugs, including sumatriptan.
A possible mechanism of beneficial effect of sumatriptan in migraine is based on the role of free radicals in migraine, as sumatriptan has direct scavenging activity on free radicals and nitric oxide. Sumatriptan action in migraine may be exerted through presynaptic 5HT1B/1D receptors in the dorsal horn to block synaptic transmission between axon terminals of the peripheral trigeminovascular neurons and cell bodies of their central counterparts. There is an increase in the rate of brain serotonin synthesis during migraine attacks, and triptans exert a negative feedback regulation of brain serotonin synthesis along with modulation of pain pathways. The effect of sumatriptan in migraine depends on the integrity of the blood-brain barrier. Cortical-spreading depression during migraine aura disrupts sodium-hydrogen exchanger type 1 (NHE1), an antiporter, which plays a role in blood-brain barrier integrity and homeostasis of intracellular pH in the brain (17). Although this disruption increases the uptake of sumatriptan into the brain, there may be variations in clinical response. The protective role of NHE1 in the central nervous system suggests that normalization of pH homeostasis by targeting NHE1 function or surface expression could be a unique therapeutic approach to enhance the efficacy of sumatriptan.
Pharmacokinetics. Important features include the following:
| • The bioavailability after subcutaneous administration is 96%. |
| • Following subcutaneous injection, maximum plasma concentration is reached between 17 to 23 hours. |
| • Plasma protein binding is low (14% to 21%). |
| • After absorption, the drug is extensively metabolized to an inactive indoleacetic acid analog that is excreted mainly in the urine. |
Sumatriptan fast disintegrating/rapid release tablet, which is bioequivalent to conventional tablets, has faster absorption and more rapid onset of effect.
Sumatriptan usually does not cross the blood-brain barrier to produce effects on the central nervous system. Animal studies indicate that sumatriptan can cross the blood-brain barrier, and some adverse effects of sumatriptan on the brain may be due to impairment of blood-brain barrier during migraine attack (29).
Therapeutic drug monitoring. A simple and sensitive method of detection coupling ultra-performance liquid chromatography with tandem mass spectrometry has been developed and validated in phase 1 studies to analyze sumatriptan levels in human plasma (24).
Formulations and methods of administration. Sumatriptan is available as oral, intranasal, and subcutaneous injection. An autoinjector has also been developed to fulfill the clinical need for an easy-to-use and rapid-to-administer system that does not require any assembly at the onset of an attack and is preferred by the patients as shown in an open phase 3 trial (14). A needle-free sumatriptan injection, Sumavel® DosePro™ for migraine and cluster headaches, has been approved and available since 2009 (07). Absorption of sumatriptan delivered by self-dissolving microneedles is like that observed after subcutaneous injection and is associated with high bioavailability (approximately 90%), which is much higher than that produced by oral administration (31).
Transdermal delivery of sumatriptan by an iontophoresis patch, which uses an electrical current to propel sumatriptan across intact skin and into underlying tissue, has been tested in a phase 1 study (25). A linear relationship was observed between total applied current and sumatriptan delivery to reach therapeutic blood levels. Pharmacokinetic studies have shown that iontophoretic delivery of sumatriptan achieves detectable plasma concentrations 15 minutes after activation with a maximum mean serum concentration of 22 ng/ml (30). Transdermal delivery has several advantages over current formulations, including avoidance of the gastrointestinal tract, controlled and sustained delivery, and convenient administration (22). In 2013, the United States Food and Drug Administration approved sumatriptan iontophoretic transdermal system (Zecuity®) for the acute treatment of migraine with or without aura in adults. Zecuity® is a single-use, battery-powered patch that actively delivers sumatriptan through the skin and provides relief of both migraine headache pain and migraine-related nausea. AVP-825 (ONZETRA® Xsail®), a breath-powered delivery system for sumatriptan dry powder, has been approved by the Food and Drug Administration for the acute treatment of migraine attacks with or without aura in adults. A single dose of AVP-825 (22 mg) delivers 15 to 16 mg sumatriptan and produces significantly lower exposure than oral or injectable formulations, which may translate into a better safety/tolerability profile (26). It has been shown to have a rapid onset of action and, unlike the traditional nasal sprays, does not drip down into the throat (28). An in situ gel of sumatriptan-loaded nano-transferosomes has been developed as a promising noninvasive drug delivery system for treating migraine by enhancing the bioavailability and sustaining the drug release (20).
