Nausea Associated with Dihydroergotamine Is a Function of Maximum Concentration and Not Route of Administration (P03.238)

Kellerman, Donald J.; Kori, Shashidhar; Forst, Amy

doi:10.1212/wnl.78.1_meetingabstracts.p03.238

Cited by 2 publications

(2 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A lower C max compared to the C max reported for IV administration of DHE may be a possible explanation. 25 In conclusion, STS101 showed a favorable tolerability profile in healthy subjects and resulted in DHE plasma concentrations comparable to IM DHE and higher than Migranal. Based on this data, STS101 is expected to provide rapid pain relief, improvement in functionality and excellent 2-hour and sustained pain freedom rates.…”

Section: Discussionmentioning

confidence: 76%

See 1 more Smart Citation

A Phase 1, Randomized, Open‐Label, Safety, Tolerability, and Comparative Bioavailability Study of Intranasal Dihydroergotamine Powder (STS101), Intramuscular Dihydroergotamine Mesylate, and Intranasal DHE Mesylate Spray in Healthy Adult Subjects

Albrecht¹,

Iwashima²,

Dillon³

et al. 2020

Headache

View full text Add to dashboard Cite

Objective To investigate and compare the safety and the pharmacokinetics of dihydroergotamine (DHE) after administration of intranasal DHE powder (STS101), intranasal DHE spray (Migranal®), and intramuscular (IM) DHE injection in healthy subjects. Methods This was a 2‐part, active‐controlled, 3‐period crossover study over 3 weeks, separated by 1‐week washout periods. In part 1, 3 ascending dosage strengths of STS101 (1.3, 2.6, and 5.2 mg) were administered to 15 healthy subjects with no history of migraine. In part 2, 27 healthy subjects were administered 1 dose each of STS101 5.2 mg, Migranal DHE Mesylate Liquid Nasal Spray 2.0 mg, and IM DHE Mesylate 1.0 mg in a randomized order. Liquid chromatography, tandem mass spectrometry was used to determine plasma levels of DHE and its major metabolite, 8′OH‐DHE. Pharmacokinetic parameters (Cmax, Tmax, AUC0‐2 h, AUC0‐48 h, AUC0‐inf, and t1/2) for DHE and metabolite were calculated. Geometric means and 90% confidence intervals of log‐transformed data were calculated and the ratio of means compared. Safety was evaluated by monitoring adverse events, vital signs, electrocardiograms, subjective and objective assessments of nasal signs and symptoms, and changes in laboratory parameters. The study is registered as NCT03874832. Results Forty‐three subjects were enrolled and received study medication. Forty completed all study activities, 14 in part 1 and 26 in part 2. In part 1, DHE plasma levels showed a dose‐dependent increase, with STS101 5.2 mg reaching a mean Cmax of 1870 pg/mL with a Tmax of 23 minutes. In part 2, STS101 5.2 mg showed rapid absorption, achieving mean DHE plasma concentrations of 1230 and 1850 pg/mL at 10 and 15 minutes after administration, respectively. In comparison to Migranal, STS101 5.2 mg showed approximately 2‐fold higher Cmax (2175 vs 961 pg/mL), AUC0‐2 h (2979 vs 1316 h × pg/mL), and AUC0‐inf (12,030 vs 6498 h × pg/mL), respectively. The mean AUC0‐inf of STS101 5.2 mg was comparable to IM DHE (12,030 vs 13,650 h × pg/mL). STS101 5.2 mg showed substantially lower variability compared to Migranal for Cmax (41% vs 76%), AUC0‐2 h (39% vs 75%), and AUC0‐inf (39% vs 55%). The incidence of treatment emergent AEs (TEAEs), all mild and transient, reported in parts 1 and 2 combined was 9/15 (60%), 5/15 (33%), and 16/41 (39%) of the subjects after 1.3, 2.6, and 5.2 mg STS101, respectively, and 4/26 (15%) and 5/27 (19%) of the subjects after IM DHE and Migranal, respectively. Conclusion STS101 showed rapid absorption, achieving effective DHE plasma concentrations within 10 minutes. It achieved substantially higher Cmax, AUC0‐2 h and AUC0‐inf, compared to Migranal suggesting potentially better efficacy than Migranal. Its variability was better than Migranal, thus offering improved consistency of response. AUC0‐inf was comparable to IM DHE, suggesting prolonged action and low recurrence. Additionally, the Cmax was sufficiently low to avoid any significant nausea reported with IV DHE. Thus, STS101 is an easy to administer, non‐injected, acute treatment for mig...

show abstract

Section: Discussionmentioning

confidence: 76%

“…There was a notable absence of nausea and vomiting with STS101, which is a major limitation of IV DHE. A lower C max compared to the C max reported for IV administration of DHE may be a possible explanation …”

Section: Discussionmentioning

confidence: 84%

A Phase 1, Randomized, Open‐Label, Safety, Tolerability, and Comparative Bioavailability Study of Intranasal Dihydroergotamine Powder (STS101), Intramuscular Dihydroergotamine Mesylate, and Intranasal DHE Mesylate Spray in Healthy Adult Subjects

Albrecht¹,

Iwashima²,

Dillon³

et al. 2020

Headache

View full text Add to dashboard Cite

show abstract

New characterization of dihydroergotamine receptor pharmacology in the context of migraine: utilization of a β-arrestin recruitment assay

McConnachie,

Goadsby,

Vann

et al. 2023

Front. Neurol.

View full text Add to dashboard Cite

IntroductionDihydroergotamine mesylate (DHE) is an established effective acute therapy for migraine and is often characterized by its broad receptor pharmacology. Knowledge of DHE pharmacology largely comes from studies employing older methodologies.ObjectiveTo assess DHE receptor activity using high-throughput methods to screen for functional ß-arrestin activity at G protein–coupled receptors (GPCRs).MethodsFunctional receptor activities of DHE and sumatriptan succinate (both 10 μM) were screened against 168 GPCRs using the gpcrMAX assay. Agonist and antagonist effects were considered significant if receptor activity was >30% or inhibited by >50%, respectively. Radiolabeled ligand binding assays were performed for DHE (0.01–300 nM for 5-HT3 and 4E; 0.3–10,000 nM for 5-HT1B, α-adrenergic2B [i.e., α2B-adrenoceptor], D2, and D5) to assess specific binding to select receptors.ResultsDHE (10 μM) exhibited agonist activity at α-adrenergic2B, CXC chemokine receptor 7 (CXCR7), dopamine (D)2/5, and 5-hydroxytryptamine (5-HT)1A/1B/2A/2C/5A receptors and antagonist activity at α-adrenergic1B/2A/2C (i.e., α1B/2A/2C-adrenoceptors), calcitonin receptor–receptor activity modifying protein 2 (CTR-RAMP2) or amylin 2 (AMY2), D1/3/4/5, and 5-HT1F receptors. Sumatriptan succinate (10 μM) exhibited agonist activity at the 5-HT1B/1E/1F/5A receptors. DHE demonstrated a half-maximal inhibitory concentration (IC50) of 149 nM at the 5-HT1F receptor and a half-maximal effective concentration (EC50) of 6 μM at the CXCR7 receptor. DHE did not bind to the 5-HT3 receptor at concentrations up to 300 nM and bound poorly to 5-HT4E and D5 receptors (IC50 of 230 and 370 nM, respectively). DHE bound strongly to the D2, 5-HT1B, and α-adrenergic2B receptors (IC50 of 0.47, 0.58, and 2.8 nM, respectively).ConclusionBy using a high-throughput β-arrestin recruitment assay, this study confirmed the broad receptor profile of DHE and provided an update on DHE receptor pharmacology as it relates to migraine.

show abstract

Nausea Associated with Dihydroergotamine Is a Function of Maximum Concentration and Not Route of Administration (P03.238)

Cited by 2 publications

References 0 publications

A Phase 1, Randomized, Open‐Label, Safety, Tolerability, and Comparative Bioavailability Study of Intranasal Dihydroergotamine Powder (STS101), Intramuscular Dihydroergotamine Mesylate, and Intranasal DHE Mesylate Spray in Healthy Adult Subjects

A Phase 1, Randomized, Open‐Label, Safety, Tolerability, and Comparative Bioavailability Study of Intranasal Dihydroergotamine Powder (STS101), Intramuscular Dihydroergotamine Mesylate, and Intranasal DHE Mesylate Spray in Healthy Adult Subjects

New characterization of dihydroergotamine receptor pharmacology in the context of migraine: utilization of a β-arrestin recruitment assay

Contact Info

Product

Resources

About