Assessing acute systemic effects of an inhaled drug with serial echocardiography: a placebo-controlled comparison of inhaled and intravenous dihydroergotamine.
OBJECTIVE
MAP0004 is an investigational product which delivers dihydroergotamine (DHE) through the lung via a breath-synchronized metered dose inhaler. The objective of this study was to compare the acute effects of orally inhaled and intravenous (IV) DHE to placebo on maximum change and area under the curve for pulmonary arterial systolic pressure (PASP).


METHODS
A randomized, double-blind, placebo-controlled, 3-period, crossover study of 24 health adults. Trial registration NCT01089062. Study assessments included pharmacokinetics, electrocardiograms (ECG), and validated echocardiographic (Doppler)-derived measures of PASP by echocardiogram. The primary endpoint was the absolute change in calculated PASP using area under the curve, 0 to 2 hours (AUC(0-2h)).


RESULTS
The change in PASP with IV DHE was significantly different than MAP0004 and placebo (AUC(0-2h)2857, 2624, and 2453 mmHg*min, respectively). After a second dose of MAP0004, AUC(0-4h) remained lower with MAP0004 than with a single dose of IV DHE. Adverse events were more common with IV DHE than with MAP0004 or placebo. None of the treatments produced clinically significant changes in PASP or other cardiac parameters. Changes in PASP were significantly smaller with MAP0004 compared with IV DHE.


CONCLUSIONS
These results indicate the effects 1 mg of orally inhaled DHE on the cardiovascular system are less than with 1 mg of IV DHE, and that serial echocardiography can be a useful noninvasive means of assessing acute systemic effects.
Duke Clinical Research Unit, Division of Clinical Pharmacology, Duke University School of Medicine, Durham, NC, USA.
Robert J
RJ
Noveck
Pamela S
PS
Douglas
Shein-Chung
SC
Chow
Barry
B
Mangum
Shashidhar
S
Kori
Donald J
DJ
Kellerman
D000280:Administration, Inhalation; D061605:Administration, Intravenous; D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D004087:Dihydroergotamine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004311:Double-Blind Method; D004452:Echocardiography; D005260:Female; D006801:Humans; D008297:Male; D036501:Metered Dose Inhalers; D008875:Middle Aged; D008881:Migraine Disorders / Q000188:drug therapy; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D013599:Systole / Q000187:drug effects
D004087:Dihydroergotamine
MAP0004; dihydroergotamine; echo; echocardiogram; inhaled; intravenous; pulmonary artery systolic pressure