Relationship of dihydroergotamine pharmacokinetics, clinical efficacy, and nausea-A narrative review

To assess the relationships between dihydroergotamine (DHE) pharmacokinetic (PK) parameters, clinical efficacy, and nausea incidence to determine a DHE PK profile that optimizes efficacy while minimizing adverse events (AEs), particularly nausea.

Dihydroergotamine is a widely used option for the acute treatment of migraine. Although multiple DHE dosage forms, with varying PK and AE profiles, have been evaluated in randomized controlled trials (RCTs), the relationships between PK profile, efficacy, and the common DHE-related AE, nausea, have not been comprehensively evaluated.

A literature search identified RCTs evaluating the efficacy (2-h pain relief [2hPR]) of different DHE dosage forms. The PK profiles for these DHE dosage forms were determined from published literature. Univariate regression analyses were performed to determine the PK parameters that best predicted 2hPR across DHE dosage forms. The relationship between maximum plasma concentration (C_max) and nausea incidence for various dosage forms was determined from published Phase 1 trials.

The literature search identified nine RCTs with DHE dosage forms that reported 2hPR: DHE liquid nasal spray (four studies), DHE administered subcutaneously (three), and DHE administered via oral pulmonary inhalation (two). The DHE PK parameters that best predicted 2hPR rates were C_max and area under the curve from time zero to 0.5 h post-dose (AUC_0-0.5h) (R² = 0.59 for each). Across Phase 1 trials, nausea incidence was minimal when C_max was <2500 pg/mL but increased in a log-linear manner when C_max exceeded ~2500 pg/mL.

The maximum concentration and AUC over the first 30 min following DHE administration were associated with increasing rates of 2hPR and a C_max below ~2500 pg/mL was associated with low incidences of nausea. We suggest that this may be an optimal profile for a DHE delivery form. Further research to test this hypothesis is warranted.