Effect of hepatic impairment on the pharmacokinetics of zolmitriptan.
Zolmitriptan, an oral 5HT1D agonist for the acute treatment of migraine, is cleared from the systemic circulation mainly by hepatic metabolism. Consequently, changes in hepatic function may result in changes in the pharmacokinetics of zolmitriptan. This open, parallel-group study was conducted to compare the pharmacokinetics and tolerability of a single 10-mg dose of zolmitriptan in healthy subjects and patients with hepatic impairment. A total of 37 participants entered and completed the study, including 10 healthy volunteers, 11 patients with moderate hepatic impairment, 10 patients with severe hepatic impairment without ascites, and 6 patients with severe hepatic impairment with ascites. The metabolism of zolmitriptan was reduced in patients with severe hepatic impairment compared with healthy subjects, resulting in higher peak plasma concentrations (47%), increased exposure (226%), and prolonged half-life (157%). The changes were similar in the presence and absence of ascites. Smaller changes were observed in patients with moderate hepatic impairment. Plasma concentrations of the three major metabolites of zolmitriptan were reduced in the patients with hepatic impairment. Patients with moderate hepatic impairment require no dosage adjustment, but the recommended daily intake of zolmitriptan may need to be reduced in patients with severe hepatic impairment.
Dixon
R
R
Zeneca Pharmaceuticals, Macclesfield, Cheshire, UK.
French
S
S
Kemp
J
J
Sellers
M
M
Leclerc
V
V
Delvaux
M
M
Rautureau
J
J
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001711:Biotransformation; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D006207:Half-Life; D006801:Humans; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010080:Oxazoles / Q000009:adverse effects / Q000493:pharmacokinetics*; D023303:Oxazolidinones; D017366:Serotonin Receptor Agonists / Q000009:adverse effects / Q000493:pharmacokinetics*; D014363:Tryptamines
D010080:Oxazoles; D023303:Oxazolidinones; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C089750:zolmitriptan