TY - JOUR
T1 - Lack of drug interaction between the migraine drug MAP0004 (orally inhaled dihydroergotamine) and a CYP3A4 inhibitor in humans
AU - Kellerman, D.
AU - Kori, S.
AU - Forst, A.
AU - Chang, J.
AU - Febbraro, S.
AU - Wutann, L.
AU - Thomas, T.
AU - Taylor, G.
AU - Dodick, D. W.
PY - 2012/1
Y1 - 2012/1
N2 - Background: Dihydroergotamine (DHE), a proven migraine treatment, currently has product labeling warning against concomitant use of CYP3A4 inhibitors because of potential drug interactions. However, no reported studies of such interactions with DHE administered by any route are available.Methods: The pharmacokinetics (PK) of MAP0004, an investigative inhaled DHE formulation, were assessed in human subjects with and without CYP3A4 inhibition by ketoconazole to evaluate the potential for drug interaction, elevation of DHE levels, and increased adverse effects.Results: After MAP0004 alone vs. MAP0004 plus ketoconazole, the DHE maximum concentrations (Cmax) and area-under-the-curve (AUC0-48 and AUC0-∞) were not statistically significantly different nor was the Cmax of the primary metabolite, 8'-OH-DHE. A difference in 8'-OH-DHE AUCs was observed between MAP0004 with and without ketoconazole; however, the concentrations were very low. MAP0004 was well tolerated after both treatments.Conclusions: This study demonstrated that CYP3A4 inhibition had little to no effect on DHE PK after MAP0004 administration, apparently because of its high systemic and low gastrointestinal bioavailability. CYP3A4 inhibition slowed elimination of the metabolite 8'-OH-DHE, but concentrations were too low to be pharmacologically relevant.
AB - Background: Dihydroergotamine (DHE), a proven migraine treatment, currently has product labeling warning against concomitant use of CYP3A4 inhibitors because of potential drug interactions. However, no reported studies of such interactions with DHE administered by any route are available.Methods: The pharmacokinetics (PK) of MAP0004, an investigative inhaled DHE formulation, were assessed in human subjects with and without CYP3A4 inhibition by ketoconazole to evaluate the potential for drug interaction, elevation of DHE levels, and increased adverse effects.Results: After MAP0004 alone vs. MAP0004 plus ketoconazole, the DHE maximum concentrations (Cmax) and area-under-the-curve (AUC0-48 and AUC0-∞) were not statistically significantly different nor was the Cmax of the primary metabolite, 8'-OH-DHE. A difference in 8'-OH-DHE AUCs was observed between MAP0004 with and without ketoconazole; however, the concentrations were very low. MAP0004 was well tolerated after both treatments.Conclusions: This study demonstrated that CYP3A4 inhibition had little to no effect on DHE PK after MAP0004 administration, apparently because of its high systemic and low gastrointestinal bioavailability. CYP3A4 inhibition slowed elimination of the metabolite 8'-OH-DHE, but concentrations were too low to be pharmacologically relevant.
KW - CYP3A4
KW - MAP0004
KW - Migraine
KW - drug interaction
KW - inhaled dihydroergotamine
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U2 - 10.1177/0333102411432299
DO - 10.1177/0333102411432299
M3 - Article
C2 - 22174351
AN - SCOPUS:84856193424
SN - 0333-1024
VL - 32
SP - 150
EP - 158
JO - Cephalalgia
JF - Cephalalgia
IS - 2
ER -