Reduced Adverse Event Profile of Orally Inhaled DHE (MAP0004) vs IV DHE: Potential Mechanism

Background.— MAP0004 is a novel orally inhaled formulation of dihydroergotamine mesylate (DHE) currently in development that has been clinically observed to provide rapid (～10 minutes) therapeutic levels of DHE but with lower rates of adverse effects (dizziness, nausea, and paresthesia) compared with intravenous (IV) dosing. Receptor‐based mechanistic studies were conducted to determine if differences between IV DHE and inhaled DHE (MAP0004) binding and functional activity were responsible for the improved adverse event profile. Methods.— Radioligand competitive binding assays were performed at adrenergic (α1 [non‐specific], α2A, α2B, α2C, β), dopaminergic (D; D₁, D₂, D₃), and at serotonergic (5‐HT; 5‐HT_1A, 5‐HT_1B, 5‐HT_1D, 5‐HT_2A, 5‐HT_2C, 5‐HT₃, 5‐HT₄, 5‐HT_5A, 5‐HT₆, 5‐HT₇) receptors. Binding assays were also conducted for the major metabolite of DHE, 8’‐hydroxy‐DHE (8’‐OH‐DHE). Subsequent functional receptor assays were also performed at 5‐HT_1B, 5‐HT_1D, 5‐HT_2A, 5‐HT_2C, 5‐HT₃, D₂, α1A, α2A, α2B, β1, and β2 and muscarinic receptors to ensure that observed receptor binding translated into potential functional response. Results.— For competitive binding studies, DHE demonstrated extensive activity at IV C_max for all 5‐HT receptors tested, except 5‐HT₃ and 5‐HT₄, and α1, α2A, α2B, α2C, and D₃ receptors. DHE concentrations used in the studies were equal to the peak plasma concentrations (C_max) observed in human subjects following IV DHE 1.0 mg (the standard approved dose), and 2 and 4 inhalations MAP0004 which, respectively, produced systemic circulation levels of DHE equivalent to 0.44 mg and 0.88 mg administered IV. MAP0004 binding activity at the C_max concentrations was lower than IV DHE and no binding was observed for the 8’‐OH‐DHE metabolite. However, MAP0004 preserved potent agonist action at key anti‐migraine 5‐HT_1B and 5‐HT_1D receptors, even at the lower C_max concentrations. Functional binding studies displayed similar results whereby IV DHE C_max concentrations invoked strong agonist/antagonist responses, for instance at adrenergic and 5‐HT_2C receptors, which could have been responsible for dizziness. Conversely, at C_max concentrations of MAP0004, inhaled DHE achieved a significantly lower response or no response at the adrenergic and 5‐HT_2C receptors. Conclusions.— The mechanism by which nausea was experienced with IV DHE – yet not with MAP0004 – was not associated with classic nausea pathways/targets (dopamine, 5‐HT₃, or muscarinic receptors) or with peripheral action in the intestine via enterochromaffin cells. Importantly, the maximum DHE concentrations following MAP0004 administration were insufficient to interact with receptors implicated in cardiovascular (5‐HT_2B and β₁) and pulmonary effects (β₂, adenosine, muscarinic, and leukotriene).