Frovatriptan: a review of drug-drug interactions.
OBJECTIVE
To investigate the potential for interactions involving drugs likely to be coadministered with frovatriptan.


BACKGROUND
Frovatriptan is a new 5-hydroxytryptamine (5-HT)(1B/1D) agonist. Preclinical data suggest that the pharmacokinetic and pharmacological profile of frovatriptan may differ from that of the currently available triptans.


METHODS
The potential for interactions between frovatriptan and other drugs was investigated using in vitro methods, studies in healthy volunteers, and retrospective analysis of data from phase I trials.


RESULTS
In vitro, frovatriptan was principally metabolized by cytochrome P-450 (CYP) 1A2 but was found not to be an inhibitor or inducer of this or other CYP isoenzymes. Frovatriptan was only a weak inhibitor of monoamine oxidase at very high concentrations in vitro and was not a substrate for this enzyme (unlike some other triptans). Coadministration with moclobemide, at doses known to inhibit monoamine oxidase-A, did not affect the pharmacokinetics of frovatriptan. Binding to plasma proteins was low (15%), and binding to erythrocytes was moderate (60%) and unlikely to be a source of interaction with other drugs. The pharmacokinetics of frovatriptan were not affected by moderate alcohol intake. There were slight increases in area under the curve and maximum concentration on concomitant administration with the combined oral contraceptives, propranolol, and fluvoxamine; and slight decreases in these parameters on concomitant administration with ergotamine and in tobacco smokers; these findings were considered to have no clinical significance in view of frovatriptan's large therapeutic index (well tolerated at doses ranging from 2.5 to 40 mg). These effects can be attributed primarily to modification of CYP1A2 activity but their impact is limited, probably due to frovatriptan also undergoing renal clearance and the likely role of blood cell binding in controlling the amount of unbound drug available for elimination.


CONCLUSIONS
Because it has no inhibitory or inducing effect on CYP isoenzymes and is only slightly bound to plasma proteins, it is unlikely that frovatriptan will alter the pharmacokinetics of concomitantly administered drugs. Frovatriptan, therefore, appears to have a low risk of interaction with other drugs, and adjustments of dose are unlikely to be required when it is coadministered with other agents.
Buchan
P
P
Vernalis Ltd, Winnersh,UK.
Wade
A
A
Ward
C
C
Oliver
S D
SD
Stewart
A J
AJ
Freestone
S
S
D000208:Acute Disease; D000818:Animals; D019540:Area Under Curve; D002227:Carbazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008881:Migraine Disorders / Q000188:drug therapy*; D008995:Monoamine Oxidase / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D051381:Rats; D012189:Retrospective Studies; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D014363:Tryptamines
D002227:Carbazoles; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; D019388:Cytochrome P-450 CYP1A2; D008995:Monoamine Oxidase; C108128:frovatriptan