Comparison of Early Plasma Exposure of DHE following Delivery by Nasal, Oral Inhalation, or Intravenous Administration
posted in Presentations by Marjorie Diddams
Poster presented at AHS 2019 Annual Meeting, poster #P134, selected for oral presentation.
Authors: Kelsey Satterly, Stephen Shrewsbury, John Hoekman
The objective of this study is to compare plasma exposure in the first two hours following administration of dihydroergotamine mesylate (DHE) by INP104 (POD® nasal), Migranal® Nasal Spray, D.H.E. 45® (IV) or MAP0004 (oral inhalation) using data obtained from the STOP 101 study and literature reports. IV DHE is a reliable and effective treatment for migraine approved in the US in 1946 (Silberstein and Kori, 2013). DHE plasma exposure in the first 2 hours is critical to migraine pain relief (FDA guidance; Kellerman, 2013), justifying an emphasis on AUC0–2hr and Cmax when assessing novel DHE products. Further, while the Cmax is important for efficacy, research suggests that a high Cmax may predict a high rate of adverse events (Shrewsbury, 2008; Jividen, 2011; Silberstein, 2014). INP104, a novel drug-device combination product in Phase 3 clinical development, targets delivery of a liquid DHE formulation to the upper nasal cavity using the Precision Olfactory Delivery (POD®) device.
(1) PK results from STOP 101, a Phase 1, single dose, safety, tolerability, and bioavailability study of healthy subjects who received INP104 (1.45 mg), Migranal Nasal Spray (2.0 mg), or D.H.E. 45 IV (1.0 mg) in a 3-way, 3-period crossover were compared.
(2) Trends of DHE PK, efficacy, and adverse events related to Cmax reported in the literature were studied and are described.
AUC0-2hr following administration of INP104 (1.45 mg), Migranal (2 mg), and D.H.E 45 (1 mg IV) was 1603, 387.5, and 3022 hr*pg/mL, respectively, in the STOP 101 trial. Cmax values were highest following D.H.E. 45 (IV) at 14190 pg/mL followed by INP104 at 1301 pg/mL and Migranal at 299.6 pg/mL. A literature report describing the PK of orally inhaled DHE 1 mg (MAP0004: clinically developed but never marketed due to CMC challenges) states an AUC0-2hr value of 1447 hr*pg/mL (Kellerman, 2013). Further, research from a Phase 2 trial with MAP0004 reports onset of pain relief in migraineurs as early as 10 minutes and only 1 incidence of nausea (Aurora, 2009). Lastly, a review of the literature suggests that the probability of nausea is <2% when plasma DHE Cmax is ≤5,000 pg/mL, and at 13,400 pg/mL, the probability of nausea is ≥50% (Jividen, 2011; Silberstein, 2014).
Delivery of INP104, DHE by the POD device, results in high plasma exposure to DHE in the first 2 hours, a goal for acute migraine products to enable potential pain relief. Further, an approximate 10-fold reduction in Cmax following DHE administration by INP104 may lead to more favorable tolerability compared to IV DHE.
Aurora SK, Rozen TD, Kori SH, Shrewsbury SB. Headache, 2009; 49:826-837.
FDA Guidance for Industry: Migraine: Developing Drugs for Acute Treatment. February 2018.
Kellerman DJ, Forst A, Combs DL, Borland S, Kori S. J Aer Med Pul Drug Del., 2013; 26(5): 297-306.
Shrewsbury SB, Jeleva M, Satterly KH, Lickliter J, Hoekman J. Headache, 2019; 0:1-16.
Shrewsbury S, Cook RO, Taylor G, Edwards C, Ramadan NM. Headache, 2008; 48: 355-367.
Silberstein S. Expert Opinion on Pharmacotherapy, 2012; 13:13, 1961-1968.
Jividen H. Nausea associated with DHE is a function of maximum concentration and not route of administration. 53rd Annual Meeting of the American Headache Society, Washington, DC, June 2-5, 2011.
Silberstein SD, Basile AS, Kellerman D, Davar G. Relationship between plasma dihydroergotamine concentrations and the occurrence of nausea after treatment with orally inhaled DHE. 56th Annual Meeting of the American Headache Society, Los Angeles, June 26-29, 2011.