Key result
Coadministration of avitriptan and propranolol resulted in a 20% increase in propranolol AUC without altering avitriptan pharmacokinetics, which was deemed not clinically significant.
Why the study?
Does coadministration of avitriptan and propranolol alter their pharmacokinetics in healthy subjects?
Does coadministration of avitriptan and propranolol alter their pharmacokinetics in healthy subjects?
Coadministration of avitriptan and propranolol results in minor pharmacokinetic changes that are not clinically significant, suggesting avitriptan can be safely added to steady-state propranolol for migraine therapy.
No clinically significant PK interaction in healthy volunteers; leaves open effects in migraine patients on chronic 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.
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Marathe et al. (1998) studied Healthy subjects. Avitriptan and propranolol coadministration vs. Avitriptan and propranolol administered separately was evaluated on Pharmacokinetics of avitriptan and propranolol. Coadministration of avitriptan and propranolol resulted in a 20% increase in propranolol AUC without altering avitriptan pharmacokinetics, which was deemed not clinically significant.
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