A pharmacokinetic interaction study of avitriptan and propranolol.
OBJECTIVE
To assess whether a clinically significant change in the pharmacokinetics of avitriptan and propranolol is observed in healthy subjects after coadministration of the two drugs.


METHODS
The pharmacokinetics of avitriptan and propranolol were investigated when the two drugs administered separately and when two 150 mg doses of avitriptan 2 hours apart were added to a steady-state regimen (80 mg twice a day) of propranolol. The pharmacokinetics of metabolites of avitriptan (N-desmethylavitriptan, methoxypyrimidinyl piperazine, and O-desmethylavitriptan) and the pharmacokinetics of 4-hydroxypropranolol were also assessed.


RESULTS
Administration of avitriptan alone and together with propranolol resulted in small increases in mean blood pressure and small decreases in heart rate. Administration of propranolol resulted in lowering of blood pressure and heart rate consistent with the beta-blocking actions of propranolol. There were no changes in the pharmacokinetics of avitriptan after coadministration with propranolol. However, area under the plasma concentration-time curve (AUC) of propranolol showed a 20% increase after coadministration with avitriptan, whereas the AUC of 4-hydroxypropranolol significantly decreased. Avitriptan therefore appeared to affect the metabolism of propranolol to 4-hydroxypropranolol. The peak plasma concentration and AUC for N-desmethylavitriptan and the AUC for methoxypyrimidinyl piperazine also showed statistically significant increases (about 25%) when avitriptan was coadministered with propranolol.


CONCLUSIONS
Considering the wide safety margin of propranolol, the increase in the exposure is not clinically significant. The increase in the exposure to the metabolites of avitriptan is also not considered to be clinically significant because the metabolite contribution to the pharmacologic activity or side effects is expected to be minimal. Based on these findings, avitriptan may be added to a steady-state regimen of propranolol as an abortive antimigraine therapy.
Marathe
P H
PH
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
Greene
D S
DS
Kollia
G D
GD
Barbhaiya
R H
RH
D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics*; D008297:Male; D011433:Propranolol / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000493:pharmacokinetics*; D014363:Tryptamines
D000319:Adrenergic beta-Antagonists; D007211:Indoles; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D014363:Tryptamines; C001422:4-hydroxypropranolol; C103231:avitriptan; D011433:Propranolol