Comparison of Early Plasma Exposure of DHE following Delivery by Nasal, Oral Inhalation, or Intravenous Administration
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.
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