THE ABSOLUTE BIOAVAILABILITY AND EFFECT OF FOOD ON THE PHARMACOKINETICS OF ZOLMITRIPTAN IN HEALTHY-VOLUNTEERS

Aims Zolmitriptan (Zomig (formerly 311C90)) is a novel 5-HT1B/1D recep tor agonist developed for the acute oral treatment of migraine. A high ly sensitive LCMS-MS assay has been developed which allows quantificat ion of plasma concentrations of zolmitriptan and its active metabolite , 183C91, after therapeutic doses. Two studies using this assay method were conducted to investigate the pharmacokinetics, including absolut e bioavailability, of 2.5 and 5 mg oral doses of zolmitriptan in men a nd women, the dose-proportionality of 2.5, 5 and 10 mg doses and the e ffect of food on the pharmacokinetics of a 5 mg oral dose. Methods Two randomized, balanced, open-label, 4-period crossover studies were con ducted in a total of 32 healthy volunteers. The first study determined the absolute bioavailability of 2.5 and 5 mg doses of zolmitriptan an d compared the pharmacokinetics in men and women. The second study exa mined the dose-proportionality in pharmacokinetics after fasting doses of 2.5, 5 and 10 mg, and the effect of food on a 5 mg dose. Blood pre ssure, heart rate, EGG, clinical chemistry, haematology and adverse ev ents were also monitored. Results The mean (s.d.) absolute oral bioava ilability was 0.41 (0.14 and 0.40) 0.09 after 2.5 mg and 0.48+/-0.14 a nd 0.36+/-0.07 after 5 mg in women and men, respectively. Without adju stment for bodyweight, plasma concentrations of zolmitriptan, but not 183C91, were higher in women than men. Mean (+/-s.d.) AUC was 32.7+/-1 0.1 and 60.2+/-26.8 ng ml(-1) h after 5 mg in men and women, respectiv ely (95% CI for ratio 0.43-0.77). After 2.5 mg mean (+/-s.d.) AUC was 18.4+/-5.4 and 23.1+/-9.9 ng ml(-1) h in men and women, respectively ( 95% CI for ratio 0.61-1.09). However, these differences were of no cli nical significance. C-max and AUC of oral zolmitriptan were dose-propo rtional and there was a 13 and 16% fall in mean zolmitriptan C-max and AUC, respectively, when administered after food. Adverse effects were minor, predominantly mild and transient, and there were no clinically significant effects on ECG, blood pressure, or laboratory parameters. Conclusions At therapeutic doses zolmitriptan has good oral bioavaila bility in healthy volunteers and has dose-proportional pharmacokinetic s that are not affected by food to any clinically relevant extent.