Research Paper A Unique Iontophoretic Patch for Optimal Transdermal Delivery of Sumatriptan Steven J. Siegel, 1,5 Carol O_Neill, 2 Louise M. Dube ´, 2 Peter Kaldeway, 3 Russell Morris, 4 David Jackson, 2 and Terri Sebree 2 Received February 6, 2007; accepted April 16, 2007; published online June 19, 2007 Purpose. Migraines affect approximately 10% of the adult population worldwide. The purpose of this study was to assess the pharmacokinetic and safety profile of a novel iontophoretic sumatriptan delivery system, NP101, which uses an electrical current to propel sumatriptan across intact skin and into underlying tissue. Four unique prototype iontophoretic sumatriptan patch conditions were compared to a 6 mg subcutaneous injection and an oral 50 mg tablet of sumatriptan succinate. Materials and Methods. This was a randomized, single-center, single-dose, six-period Phase I study. Results. Patches were well tolerated with fewer adverse events than the subcutaneous injection. Adverse events that were more prevalent for NP101 than other formulations included localized sensations and reactions at the patch site. A linear relationship was observed between total applied current and sumatriptan delivery. Patches delivering 6 and 12 mA per h yielded favorable sumatriptan systemic profiles, delivering drug at a rate that maintained plasma levels above the target level (Q10 ng/ml) for greater than 7 h. Conclusions. This study met the initial objective to define the dose–current relationship in humans as well as delimiting specific current and current density targets for a well tolerated patch design that can deliver therapeutic drug levels for longer periods than currently possible. KEY WORDS: clinical trial; iontophoresis; migraine; phase I; sumatriptan. INTRODUCTION Migraine is a condition that affects approximately 10% of the adult population worldwide, yielding approximately 600 million people with about 28 million in the USA alone (1–3). In addition to headache pain, migraine can be associated with a variety of other symptoms, including diarrhea, cold extremities, facial pallor, nausea, vomiting and sensitivity to external stimuli such as light, sounds or odors. Such migraines typically last for up to 24 h, but can range from 4 to 72 h and patients often experience migraine attacks one to two times per month. Pharmacologic interventions constitute the main- stay of treatment for migraines and are available for both acute treatment (abortive) and prevention (prophylactic). Mild migraine can often be effectively treated with over-the-counter medications including aspirin, acetaminophen, NSAIDs, and combination products that include caffeine. Triptans are the mainstay of treatment for acute migraine of moderate to severe intensity (4). When these agents are used early in the course of an attack, triptans abort more than 80% of migraines within 2h(5). However, several different triptan products are available with variation in the efficacy and tolerability of different medications in this class. Triptans are also available in a variety of formulations (oral, dissolvable tablet, nasal spray and injectable). Non-oral formulations are typically used for patients with gastrointestinal symptoms of nausea or vomiting and/or when a more rapid onset of action is desired. Triptans are thought to work by activating serotonin (5-HT) receptors on trigeminovascular nerve endings, inhib- iting the release of neurotransmitters that cause painful cranial vasodilatation. Furthermore, triptans produce active vasoconstriction and may relieve symptoms of migraine by stimulating 5-HT receptors on cranial vessels (6). Sumatrip- tan is the most widely prescribed triptan, comprising roughly half of all triptan prescriptions between 2002 and 2004. The three currently marketed sumatriptan formulations each have advantages and disadvantages. The injection and intranasal formulations offer rapid onset of action and may reduce further gastrointestinal discomfort. The injection also pro- vides a good response in most patients, but yields a higher maximum concentration that may contribute to a higher side effect burden. However, many patients do not like the 1919 0724-8741/07/1000-1919/0 # 2007 Springer Science + Business Media, LLC Pharmaceutical Research, Vol. 24, No. 10, October 2007 ( # 2007) DOI: 10.1007/s11095-007-9317-1 1 Division of Neuropsychiatry, University of Pennsylvania, Translational Research Laboratories, 125 S. 31st St. Rm. 2223, Philadelphia, Pennsylvania 19104, USA. 2 NuPathe Inc., 375 E. Elm Street, Suite 110, Conshohocken, Pennsylvania 19428, USA. 3 Kendle International Clinical Pharmacology Unit, Bolognalaan 40, Utrecht, 3584 CJ, The Netherlands. 4 Travanti Pharma Inc., 2520 Pilot Knob Rd., Suite 100, Mendota Heights, Minnesota 55120, USA. 5 To whom correspondence should be addressed. (e-mail: siegels @mail.med.upenn.edu)