Comparison of Early Plasma Exposure to DHE for Marketed and Development Stage Nasal, Inhalation, and Injectable Products
posted in Presentations by Jennifer Price
Poster presented at the 2020 AAN Annual Meeting, held virtually.
Authors: Kelsey Satterly, Stephen Shrewsbury, John Hoekman
To compare AUC0-2hr and adverse events following administration of INP104 (dihydroergotamine mesylate [DHE] by Precision Olfactory Delivery [POD®]), Migranal® Nasal Spray, D.H.E. 45® (IV), STS101 (nasal powder), and MAP0004 (oral inhalation) using data obtained from the STOP 101 study and literature reports.
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.
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 to results in published literature reports for STS101 (6 mg) and MAP00004 (1 or 2 mg). 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 hr*pg/mL, respectively, in the STOP 101 trial. Cmax values were highest following IV DHE at 14,190 pg/mL followed by INP104 (1,301 pg/mL) and Migranal (299.6 pg/mL). Adverse events were highest for IV DHE and were similar for INP104 and Migranal, despite the substantial difference in plasma exposure. Published reports for STS101 and MAP00004 report AUC0-2hr values of 2,979 and 1,447 hr*pg/mL, respectively. One literature report from a Phase 2 trial with MAP0004 reports that exceeding dose levels of >1 mg for MAP00004 provides plasma levels that result in a higher rate of adverse events absent any therapeutic gain.
AUC0-2hr of DHE that exceeds ~1,500 hr*pg/mL and high Cmax values may result in more adverse events without an enhancement of efficacy. INP104 administration results in the targeted plasma exposure to DHE in the first 2 hours, to potentially 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 K, Shrewsbury SB and Hoekman J, Comparison of Early Plasma Exposure to DHE for Marketed and Development Stage Nasal, Inhalation, and Injectable Products, AAN 2020 Science Highlights Presentations.