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 ( approximately 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 (alpha1 [non-specific], alpha2A, alpha2B, alpha2C, beta), dopaminergic (D; D(1), D(2), D(3)), and at serotonergic (5-HT; 5-HT(1A), 5-HT(1B), 5-HT(1D), 5-HT(2A), 5-HT(2C), 5-HT(3), 5-HT(4), 5-HT(5A), 5-HT(6), 5-HT(7)) 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-HT(3), D(2), alpha1A, alpha2A, alpha2B, beta1, and beta2 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-HT(3) and 5-HT(4), and alpha1, alpha2A, alpha2B, alpha2C, and D(3) 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-HT(3), 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 beta(1)) and pulmonary effects (beta(2), adenosine, muscarinic, and leukotriene).

Safety and pharmacokinetics of dihydroergotamine mesylate administered via a Novel (Tempo) inhaler.

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 C(max), t(max), AUC(0-6), AUC(0-48), AUC(0-inf), and t(1/2) 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 (t(max) approximately 12 minutes) DHE concentrations achieved after 4 actuations ( approximately 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 AUC(0-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.

Novel sustained release microspheres for pulmonary drug delivery.

A novel process for generating sustained release (SR) particles for pulmonary drug delivery is described. High purity nanoparticles of a hydrophilic, ionised drug are entrapped within hydrophobic microspheres using a spray-drying approach. Sustained release of the model drug, terbutaline sulphate (TS), from the microspheres was found to be proportional to drug loading and phospholipid content. Microspheres with a 33% drug loading exhibited sustained release of 32.7% over 180 min in phosphate buffer. Release was not significantly different in simulated lung fluids. No significant burst release was observed which suggested that nanoparticles were coated effectively during spray-drying. The absence of nanoparticles at the microsphere surface was confirmed with confocal microscopy. The sustained release microspheres were formulated as a carrier-free dry powder for inhalation, and exhibited a favourable Fine Particle Fraction (FPF) of 46.5+/-1.8% and Mass Median Aerodynamic Diameter (MMAD) of 3.93+/-0.12 microm.