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

Authors

  • Robert O. Cook PhD,

    1. From the MicroDose Therapeutx, Monmouth Junction, NJ, USA (R.O. Cook); AVI BioPharma Inc., Corvallis, OR, USA (S.B. Shrewsbury); Diamond Headache Clinic, Chicago, IL, USA (N.M. Ramadan).
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  • Stephen B. Shrewsbury MD,

    1. From the MicroDose Therapeutx, Monmouth Junction, NJ, USA (R.O. Cook); AVI BioPharma Inc., Corvallis, OR, USA (S.B. Shrewsbury); Diamond Headache Clinic, Chicago, IL, USA (N.M. Ramadan).
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  • Nabih M. Ramadan MD

    1. From the MicroDose Therapeutx, Monmouth Junction, NJ, USA (R.O. Cook); AVI BioPharma Inc., Corvallis, OR, USA (S.B. Shrewsbury); Diamond Headache Clinic, Chicago, IL, USA (N.M. Ramadan).
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  • Conflict of Interest: Robert Cook was a full-time employee of MAP Pharmaceuticals and at present serves as a paid consultant to the company. Steve Shrewsbury was a full-time employee of MAP Pharmaceuticals and at present serves as a paid consultant to the company. Nabih Ramadan serves as a consultant to MAP Pharmaceuticals and is on its scientific advisory board.

R. Cook, Product Commercialization, MicroDose Therapeutx, 4262 US Route 1, Monmouth Junction, NJ 08852-1947, USA.

Abstract

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-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2C, 5-HT3, 5-HT4, 5-HT5A, 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-HT1B, 5-HT1D, 5-HT2A, 5-HT2C, 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 Cmax 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 (Cmax) 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 Cmax 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-HT1B and 5-HT1D receptors, even at the lower Cmax concentrations. Functional binding studies displayed similar results whereby IV DHE Cmax concentrations invoked strong agonist/antagonist responses, for instance at adrenergic and 5-HT2C receptors, which could have been responsible for dizziness. Conversely, at Cmax concentrations of MAP0004, inhaled DHE achieved a significantly lower response or no response at the adrenergic and 5-HT2C 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-HT2B and β1) and pulmonary effects (β2, adenosine, muscarinic, and leukotriene).

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