Lasmiditan and Sumatriptan: Comparison of in Vivo Vascular Constriction in the Dog and in Vitro Contraction of Human Arteries

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Lasmiditan and sumatriptan: comparison of in vivo vascular constriction in the dog and in vitro contraction of human arteries

Article in Cephalalgia · September 2016

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Eloísa Rubio-Beltrán Kristian Agmund Haanes Erasmus MC Rigshospitalet

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Alejandro Labastida-Ramírez Carlos M. Villalon Erasmus MC Center for Research and Advanced Studies of the National Polytechnic Institute

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* (R)-isometheptene is being investigated in the US for attacks (21/44; 47.8%) did not require rescue medication. tension-type headache under a US IND and is not No device-related adverse events were recorded. approved for any indication. Conclusions: In this preliminary evaluation, nVNS had Conflict of interest favorable safety and tolerability and was practical and effec- Disclosure statement: tive in acutely treating migraine without aura in This study was supported by Tonix Pharmaceuticals adolescents.

Conflict of interest EHMTC-0155 Disclosure statement: POSTER SESSION D Licia Grazzi, MD, has received consultancy and advisory fees from Allergan, Inc., and electroCore, LLC. Gabriella NON-INVASIVE VAGUS NERVE Egeo, MD, PhD, has nothing to disclose. Eric Liebler is an STIMULATION (NVNS) FOR THE ACUTE employee of electroCore, LLC, and receives stock owner- TREATMENT OF MIGRAINE WITHOUT ship. Piero Barbanti, MD, PhD, has received consultancy AURA IN ADOLESCENTS: PRELIMINARY fees from Allergan, Inc., electroCore, LLC, Janssen CLINICAL EXPERIENCE Pharmaceuticals, Inc., and Lusofarmaco and advisory fees L. Grazzi1, G. Egeo2, E. Liebler3, P. Barbanti2 from Abbott Laboratories and Merck & Co., Inc. 1Carlo Besta Neurological Institute and Foundation, Headache Center, Milan, Italy EHMTC-0329 2Istituto di Ricovero e Cura a Carattere Scientifico- San POSTER SESSION D Raffaele Pisana, Headache and Pain Unit- Department of Neurological Motor and Sensorial Science, Rome, Italy LASMIDITAN AND SUMATRIPTAN: 3electroCore- LLC, Scientific- Medical and Governmental COMPARISON OF IN VIVO VASCULAR Affairs, Basking Ridge, USA CONSTRICTION IN THE DOG AND IN VITRO CONTRACTION OF HUMAN Background: Recent study results and clinical experience ARTERIES have demonstrated the safety, tolerability, and efficacy of non-invasive vagus nerve stimulation (nVNS; E. Rubio Beltran1, H. Kristian1, A. Labastida1, R. gammaCoreÕ) for the acute and prophylactic treatment de Vries1, J. Danser1, G. Michael2, S. Peter2, of migraine. nVNS has a favorable adverse event profile, J. Kovalchin3, C. Villalo´n4, A. MaassenVanDenBrink1 making it an attractive option for sensitive patient 1Erasmus MC, Div. of Pharmacology- Dept. of Internal populations. Medicine, Rotterdam, Netherlands 2CorDynamics, Chicago, USA Aim: To explore the safety, tolerability, and efficacy of 3CoLucid Pharmaceuticals, Cambridge, USA nVNS as an acute treatment of migraine without aura in 4Cinvestav-Coapa, Dept. de Farmacobiologı´a, Mexico City, adolescents. Mexico

Methods: Eight 13- to 18-year-old patients with migraine Antimigraine triptans are vasoconstrictive 5-HT1B/1D without aura according to International Classification of receptor agonists that are contraindicated in patients Headache Disorders, 3rd edition (beta version) criteria (4 to with coronary artery disease. In contrast to sumatriptan, 8 migraine days per month) were recruited. In a one-hour lasmiditan is a selective 5-HT1F receptor agonist that training workshop, the patients and their parents were lacked in vitro vasoconstrictive effects in rabbit saphenous instructed to treat attacks acutely with nVNS for one vein. To further assess the cardiovascular effects of lasmi- month. Each attack was treated with one 2-minute stimu- ditan, we studied the vascular effect of lasmiditan in dogs lation on the right side of the neck; a second stimulation and in human isolated arteries and compared it to was allowed within one hour of the first treatment. sumatriptan. Patients recorded the pain intensity of the treated attack at several prespecified time points between 30 minutes Anesthetized female beagle dogs (5.4–7.9 kg) were and 24 hours after treatment. Rescue medication was implanted with carotid and coronary artery crystals for allowed after 2 hours from device use. measurement of vascular diameter. Lasmiditan, sumatriptan and vehicle were administered by intravenous infusion Results: Of the 44 treated migraine attacks, 17 (38.6%) over 20 minutes in escalating cumulative doses ranging were pain free at one hour. Pain intensity for an additional from 0.03 to 11.13 mg/kg (n 6/group). Statistically signifi- 4/44 (9.1%) attacks decreased to mild at 2 hours. These cant decreases in both coronary¼ and carotid artery ! International Headache Society 2016 Abstracts 105

diameters occurred in the sumatriptan-treated group at marketed formulation, highlighting an unmet need for an clinically relevant doses compared to the vehicle control effective non-oral migraine medication with a rapid onset (p < 0.025). Conversely, lasmiditan was devoid of any vaso- of action. constrictive activity at all doses tested. Methods: We conducted an open-label, randomized, In human isolated blood vessels, sumatriptan induced con- single-dose, three-way crossover bioavailability study com- tractions in the proximal (Emax 44% of contraction to paring DFN-02 with 4 mg and 6 mg SC sumatriptan in 78 100 mM KCl, pEC 6.29, n 2) and distal (E 139%, healthy, fasted adults. Subjects received a single dose of 50 ¼ max pEC 6.45, n 2) coronary artery. In internal mammary each treatment with at least three days between treat- 50 ¼ artery, sumatriptan also induced contractions (Emax ments. Blood was sampled for pharmacokinetic evaluation 30 16%, pEC 5.86 0.56, n 5). and contractions of sumatriptan and DDM through 24 hours post-dose. Æ 50 Æ ¼ were augmented (Emax 79 19%, pEC50 6.42 0.66, n 5) after precontraction withÆ threshold concentrationsÆ Results: Median tmax was 10 minutes for DFN-02 com- of¼ U46619. Vehicle and lasmiditan did not contract any of pared to 15 minutes for 4 mg and 6 mg SC sumatriptan the arteries studied, either from baseline or after precon- (P <.0001). Mean sumatriptan exposure metrics were traction with U46619. similar for DFN 02 and 4 mg sumatriptan: AUC0–2 values were 35.12 and 44.82 ng*hr/ml, respectively; Thus, in canine and most importantly, in human blood AUC0- values were 60.70 and 69.21 ng*hr/mL, respec- vessels, the lack of vasoconstrictive properties of lasmidi- tively; Cmax1 values were 51.79 and 49.07 ng/mL, respec- tan may be a cardiovascular safety advantage compared to tively. DDM exposure was low (mean Cmax 1.63 ng/ml), the triptans. tmax was 30 minutes, and DDM was undetectable¼ by 4 hours. There were no serious adverse events, discontinua- Conflict of interest tions due to adverse events, or any clinically remarkable Disclosure statement: findings. This study was supported by CoLucid Pharmaceuticals Conclusions: Plasma sumatriptan concentrations of DFN-02 peaked five minutes earlier than 4 mg and 6 mg EHMTC-0010 SC sumatriptan. The rapid absorption of DFN-02 suggests POSTER SESSION D that its efficacy will be comparable to that of 4 mg SC PHARMACOKINETICS, SAFETY, AND sumatriptan. TOLERABILITY OF DFN-02, AN Financial Support: This study was funded and spon- INTRANASAL SUMATRIPTAN SPRAY sored by Promius Pharma, Princeton, NJ 08540, USA. CONTAINING A PERMEATION ENHANCER, COMPARED WITH SUBCUTANEOUS (SC) Document not received SUMATRIPTAN IN HEALTHY ADULTS Sagar Munjal1, Anirudh Gautam2, Elliot Offman3, Elimor Brand Schieber1, Kent Allenby1, Dennis EHMTC-0069 M. Fisher4 POSTER SESSION D 1Promius Pharma/Dr. Reddy’s Laboratories, Princeton, NJ VITAMIN B COMPOUND COULD BE 2Dr. Reddy’s Laboratories, Hyderabad, India EFFECTIVE IN MENSTRUAL RELATED 3Celerion, Neptune, NJ MIGRAINE 4 P Less Than, San Francisco, CA. S. Razeghi Jahromi1,2, M. Togha2 Objective: To compare the pharmacokinetic characteris- 1 Shahid-Beheshti University of Medical Sciences, School of tics of two commercial sumatriptan products, 4 mg and Nutrition and Food Technology, Tehran, Iran 6 mg SC sumatriptan with DFN-02, an intranasal formula- 2Tehran University of Medical Sciences, Headache tion comprised of sumatriptan 10 mg plus 0.20% permea- department- Iranian Center of Neurological Research- tion enhancer 1 O n Dodecyl-b-D-Maltopyranoside Neuroscience Institute, Tehran, Iran (DDM, IntravailÕ A3) in healthy adults. Background: Migraine headaches are disabling problem Background: Intranasal sumatriptan (ImitrexÕ) may be an for women with many of them experience more severe alternative for patients who refuse injections and cannot attacks before menstruation. Homocysteinemia results in tolerate oral agents, but low bioavailability and slow overproduction of homocysteic acid which in turn stimu- absorption limit the clinical utility of the currently lates the trigeminovascular system and provokes ! International Headache Society 2016

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