Objective.— We investigated the pulmonary absorption of dihydroergotamine (DHE) mesylate and compared the safety, pharmacokinetic, and metabolic profile of 4 different doses of orally inhaled DHE delivered by the Tempo™ Inhaler (MAP Pharmaceuticals Inc., Mountain View, CA, USA) with 1.0 mg intravenously (IV) administered DHE in 18 healthy subjects.
Methods.— Safety was measured by monitoring adverse events, vital signs, electrocardiograms, spirometry, and changes in biochemical and hematological laboratory values. Liquid chromatography, tandem mass spectrometry was used to determine plasma DHE levels while Cmax, tmax, AUC0-6, AUC0-48, AUC0-inf, and t1/2 of parent DHE and the major bioactive metabolite, 8′OH-DHE. Pharmacokinetic parameters and qualitative spectrograms for DHE and metabolites for all treatment groups were compared after inhaled DHE (MAP0004) and IV DHE 1.0 mg. Geometric means and 90% confidence intervals of log-transformed data were calculated and the ratio of means compared.
Results.— Inhaled DHE resulted in rapid systemic absorption with pharmacokinetic parameters of both parent DHE and 8′OH-DHE similar to those achieved after a 3-minute IV infusion. Post-peak (tmax∼12 minutes) DHE concentrations achieved after 4 actuations (∼0.88 mg respirable dose) of MAP0004 were comparable to those detected after IV administration. The systemic exposure to DHE after 6 actuations of MAP0004 was slightly greater than that achieved after IV administration (geometric mean AUC0-inf ratio = 1.24).
Conclusion.— The 4-actuation delivery was well tolerated and provided systemic levels of DHE and 8′OH-DHE slightly lower than IV administration and predicted levels.