Assessment of the Consistency of Absorption of Dihydroergotamine Following Oral Inhalation: Pooled Results from Four Clinical Studies

Kellerman, Donald J.; Forst, Amy; Combs, Daniel L.; Borland, Scott W.; Kori, Shashidhar

doi:10.1089/jamp.2012.0999

Cited by 18 publications

(45 citation statements)

References 15 publications

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“…The reported AUC 0‐2 h values showed more than 2‐fold higher DHE concentrations with STS101 compared to Migranal. The AUC 0‐2 h values also exceed previously reported data for the oral inhaled DHE product (MAP0004) and INP104, a liquid DHE formulation administered by a novel, propellant‐driven nasal delivery device, by about 2‐fold …”

Section: Discussionsupporting

confidence: 59%

“…DHE has been reported to have a long pharmacodynamic half‐life and a prolonged receptor residence time due to tight binding . Sustained high plasma concentrations beyond 2 hours (AUC 0‐inf ) may also contribute to the sustained efficacy and lower recurrence rates seen with DHE in general and especially with the IM and SC administration which provide the highest AUC 0‐inf . In this study the AUC 0‐inf for STS101 5.2 mg achieved 83% of the values of the IM DHE and 205% of the values for Migranal.…”

Section: Discussionmentioning

confidence: 56%

“…Rapid absorption of any drug for acute treatment of migraine is assumed to be critical for the onset of pain relief . The study data suggest that STS101 5.2 mg provides rapid DHE absorption achieving plasma concentrations and an AUC 0‐30 min that have been previously shown to result in an onset of clinical efficacy within about 30 minutes …”

Section: Discussionmentioning

confidence: 87%

“…STS101 (Satsuma Pharmaceuticals, Inc, South San Francisco, CA; Figs. and ) is a discreet, single‐use, drug‐device combination product designed to facilitate quick, simple, and intuitive intranasal administration of a novel DHE powder formulation that provides favorable PK properties; in particular, it results in rapid and sustained absorption via the nasal mucosa to achieve DHE plasma concentrations that have been demonstrated to be effective . By improving upon ease and speed of administration and providing favorable PK properties, STS101 may facilitate broader utilization of DHE and realization of the unique benefits of DHE by people with migraine.…”

Section: Introductionmentioning

confidence: 99%

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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

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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...

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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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

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“…Recent clinical phase 3 trials show that orally inhaled dihydro-ergotamine is effective for acute migraine treatment [ 33 ]. Even clinical interest in the therapeutical potential of ergoline hallucinogens is growing, for example, for the treatment of autism [ 34 , 35 ].…”

Section: Pharmacological Activities and Therapeutical Applications Ofmentioning

confidence: 99%

Ergot Alkaloids

Tudzynski¹,

Neubauer²

2014

Fungal Biology

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The Pharmacokinetics of Drugs Delivered to the Upper Nasal Space

Shrewsbury

2023

Pharm Med

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Assessment of the Consistency of Absorption of Dihydroergotamine Following Oral Inhalation: Pooled Results from Four Clinical Studies

Abstract: These results provide evidence of the consistency of absorption that can be achieved with the use of an appropriate metered dose inhaler, which may translate into a predictable therapeutic response.

Cited by 18 publications

References 15 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

Ergot Alkaloids

The Pharmacokinetics of Drugs Delivered to the Upper Nasal Space

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