Effects of a supratherapeutic dose of investigational orally inhaled
dihydroergotamine (MAP0004) on QT interval: a randomized, double-blind, active-
and placebo-controlled crossover study in healthy volunteers.
Author(s): Kori S, Kellerman DJ, Voloshko P, Haugen G.
Affiliation(s): MAP Pharmaceuticals, Inc, Mountain View, California 94043, USA.
Publication date & source: 2012, Clin Ther. , 34(9):1920-8
BACKGROUND: MAP0004 is an orally inhaled investigational drug containing
dihydroergotamine (DHE). Although DHE has been used for 60 years with no reported
cardiac arrhythmias, a thorough QT study had not previously been performed with
DHE.
OBJECTIVE: The objective of this study was to assess the effects of MAP0004 on
the QT interval as required for regulatory approval of a new product.
METHODS: This randomized, double-blind, placebo-controlled, 3-period crossover
study enrolled healthy volunteers. Subjects were assigned to receive, in
randomized sequence, MAP0004 at a supratherapeutic dose (3-fold the clinically
effective dose) (3.0 mg), moxifloxacin 400 mg, or inactive vehicle, each
administered with 1 placebo capsule. Triplicate ECGs were performed continuously
at baseline (day 0), before dosing, and over 24 hours after dosing in each
treatment period. The effect on the QT interval was assessed using the Fridericia
(QTcF) and individualized (QTcI) correction formulas.
RESULTS: Fifty-four healthy adults (20 men, 34 women; mean age, 28 years)
completed the trial and had measurable plasma levels of DHE after MAP0004
administration. The largest observed mean difference in QTcI between MAP0004 and
placebo was 0.08 msec, and the largest 1-sided 95% upper confidence bound was
2.24 msec, both at 30 minutes after dosing. In contrast, moxifloxacin increased
the mean QTcI between 9.57 and 11.28 msec relative to placebo, with a 1-sided
lower 95% CL between 7.23 and 8.96 msec, confirming that the assay sensitivity
was sufficient to detect MAP0004-related effects. Nausea (27.8%) was common
following MAP0004 administration but apparently did not influence the QTc
interval.
CONCLUSIONS: A supratherapeutic dose of MAP0004 was not associated with prolonged
QTc intervals. At the proposed clinical dose (1.0 mg), MAP0004 is unlikely to
affect the QT interval. MAP0004 and its primary metabolite showed no evidence for
prolongation of the QTc interval in healthy subjects according to the criteria
required from regulatory agencies. ClinicalTrials.gov identifier: NCT01191723.
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