Comparison of Early Plasma Exposure to DHE by Nasal, Oral Inhalation, or Intravenous Administration
posted in Presentations by Marjorie Diddams
Poster presented at the International Headache Congress (IHC) 2019 in Dublin, Ireland.
Authors: Kelsey H. Satterly, Stephen B. Shrewsbury, John Hoekman
To compare plasma exposure in the first two hours following administration of INP104 (dihydroergotamine mesylate [DHE] by Precision Olfactory Delivery [POD®]), 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 since 1946. DHE plasma exposure in the first 2 hours is critical to migraine pain relief, justifying an emphasis on AUC0–2hr when assessing novel DHE products. Although Cmax is also important for efficacy, research suggests that the high Cmax of IV administration may predict a higher rate of adverse events. 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 POD device.
PK results from STOP 101, a Phase 1, single dose, safety, tolerability, and bioavailability study in healthy subjects who received INP104 (1.45 mg), Migranal (2 mg), or D.H.E. 45 (IV) (1 mg) in a 3-way, 3-period crossover were compared. Trends of DHE PK, efficacy, and adverse events related to AUC0-2hr and Cmax reported in the literature were reviewed and are described.
AUC0-2hr following administration of INP104, Migranal, and D.H.E. 45 (IV) was 1,603, 387.5, and 3,022 hrpg/mL, respectively, in the STOP 101 trial. Cmax values were highest following IV DHE (14,190 pg/mL), then INP104 (1,301 pg/mL) and Migranal (299.6 pg/mL). A literature report of MAP0004 (1 mg), clinically developed but never marketed due to CMC challenges, states an AUC0-2hr value of 1,447 hrpg/mL. Another MAP0004 literature report describes onset of pain relief in migraineurs as early as 10 minutes and only 1 incidence of nausea. Lastly, a review of the literature suggests that the probability of nausea is <2% when plasma DHE Cmax is ≤5,000 pg/mL, whereas at 13,400 pg/mL, the probability of nausea is ≥50%.
INP104 administration results in high plasma exposure to DHE in the first 2 hours, a goal for acute migraine products to enable rapid and sustained pain relief, as validated by the MAP0004 clinical program. Further, the significant reduction in Cmax of DHE following INP104 treatment, relative to IV, may lead to more favorable tolerability of INP104.
Satterly KH, Shrewsbury SB, and Hoekman J. Comparison of Early Plasma Exposure to DHE by Nasal, Oral Inhalation, or Intravenous Administration IHC 2019 Abstracts. (2019). Cephalalgia, 39(1_suppl), 33-34. https://doi.org/10.1177/0333102419859835