Crossover Study Highlights Pharmacokinetic Effects of DHE Powder STS101

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STS101 demonstrated mild and predictable adverse events, suggesting potential efficacy at 5.2 mg dose for migraines.

Richard B. Lipton, MD, director of the Montefiore Headache Center

Richard B. Lipton, MD

A recently published, randomized, open-label, 5-period crossover study showed that treatment with STS101, an intranasal dihydroergotamine (DHE) powder, was safe in healthy participants, with high DHE plasma concentrations seen within 20 minutes of administration. Overall, DHE plasma concentrations were higher than that observed with liquid nasal spray (LNS) DHE mesylate.1

Led by Richard B. Lipton, MD, director of the Montefiore Headache Center, the 5-week trial assessed 3 STS101 dosage strengths (5.2, 7.0, and 8.6 mg) and 1 dose each of LNS DHE 2.0 mg and intramuscular (IM) DHE mesylate injection 1.0 mg in 36 healthy participants. Each group comprised of 7 healthy participants, aged 18 to 50 years of any race and sex, with no clinically significant abnormality identified in the medical or laboratory evaluations.

Liquid chromatography, tandem mass spectrometry (LC-MS/MS) was used to determine DHE (including its 8′OH-DHE metabolite) plasma levels and to calculate PK parameters (Cmax, Tmax, AUC0-2h, AUC0-last, AUC0-inf, and T1/2). Results showed that DHE plasma concentrations rapidly rose in all 3 STS101 treatment groups and IM DHE injection, with mean concentrations greater than 1500 pg/mL and greater than 2000 pg/mL for all STS101 dose strengths at 15 and 20 min, respectively. Following administration of STS101, the mean Cmax was 2230, 2710, and 2660 pg/mL for the 5.2, 7.0, and 8.6 mg dose strengths, respectively; meanwhile, the mean Cmax for IM and LNS DHE was 3730 and 673 pg/mL, respectively.

Overall, 3 participants did not receive every study treatment, and 1 discontinued because of elevated liver enzymes. In the STS101 groups, the variability in Cmax ranged between 35% and 41%, which was substantially lower than that of the LNS DHE, which had a coefficient of variation (%CV) of 87%. Similar results were seen for the AUC0-inf of the STS101 groups, which ranged between 37% and 45%, vs 64% for LNS DHE. The mean elimination half-life was 13.0, 13.4, 13.8, 12.4, and 16.5 for STS101 5.2, 7.0, and 8.6 mg, IM, and LNS, DHE, respectively.

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"LNS DHE use has been hampered by high plasma concentration variability leading to inconsistent and unreliable clinical performance,” study authors noted. "In this study, the variability for Cmax and AUC0-inf were substantially lower with STS101 compared to LNS DHE, suggesting STS101 may have more predictable, reliable, and robust clinical performance. Plasma concentrations observed following LNS DHE administration were similar to those reported in historical studies, despite the fact that the current study utilized different bioanalytical methods (LC–MS/MS) than in historical studies (radioimmunoassay)."

Among the 36 participants dosed with study medication, 92 treatment-emergent adverse events (TEAEs) were recorded, most of which (92%) were mild and none that were assessed as severe. TEAEs were found in 14%, 31%, and 31% of those in the STS101 5.2, 7.0, and 8.6 mg groups, respectively, and in 29% and 12% of IM DHE and LNS DHE groups, respectively. There were no deaths or serious AEs.

In the study, 1 participant on IM DHE 1.0 mg injection withdrew after showing elevated liver enzymes, and 1 participant had hypertensive urgency 7 days after dosing with 8.6 mg STS101; however, both were deemed unrelated to study treatment. Overall, the incidence of TEAEs increased with STS101 dosage, and was approximately 3 times higher for nasal AEs and nausea when comparing the 7.0 and 8.6 mg doses to the 5.2 mg dose.

"The overall frequency of nasal AEs was comparable to those of other nasal migraine products," Lipton et al wrote. "While no dose-limiting tolerability was reached, the higher rate of AEs in conjunction with only a slightly higher drug exposure for the higher STS101 dose strengths suggests that STS101 5.2 mg may be the dose that meets efficacy requirements, while avoiding local and systemic AEs."

REFERENCE
1. Lipton RB, Albrecht D, Bermundez M, Hu J, Hussey E, Levy J. A randomized, open-label, 5-period crossover study evaluating the pharmacokinetics and safety of a single dose of intranasal dihydroergotamine (DHE) powder (STS101), intramuscular DHE mesylate, and liquid nasal spray DHE in healthy adults. Headache. 2024;64(3):266-275. doi:10.1111/head.14685
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