The absolute bioavailability and effect of food on the pharmacokinetics of zolmitriptan in healthy volunteers

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Abstract
Aims Zolmitriptan (Zomig (formerly 311C90)) is a novel 5‐HT1B/1D receptor agonist developed for the acute oral treatment of migraine. A highly sensitive LCMS‐MS assay has been developed which allows quantification 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 absolute bioavailability, of 2.5 and 5 mg oral doses of zolmitriptan in men and women, the dose‐proportionality of 2.5, 5 and 10 mg doses and the effect of food on the pharmacokinetics of a 5 mg oral dose. Methods Two randomized, balanced, open‐label, 4‐period crossover studies were conducted in a total of 32 healthy volunteers. The first study determined the absolute bioavailability of 2.5 and 5 mg doses of zolmitriptan and compared the pharmacokinetics in men and women. The second study examined 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 pressure, heart rate, ECG, clinical chemistry, haematology and adverse events were also monitored. Results The mean (s.d.) absolute oral bioavailability was 0.41 (0.14 and 0.40) 0.09 after 2.5 mg and 0.48±0.14 and 0.36±0.07 after 5 mg in women and men, respectively. Without adjustment for bodyweight, plasma concentrations of zolmitriptan, but not 183C91, were higher in women than men. Mean (±s.d.) AUC was 32.7±10.1 and 60.2±26.8 ng ml−1 h after 5 mg in men and women, respectively (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 clinical significance. Cmax and AUC of oral zolmitriptan were dose‐proportional and there was a 13 and 16% fall in mean zolmitriptan Cmax 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 bioavailability in healthy volunteers and has dose‐proportional pharmacokinetics that are not affected by food to any clinically relevant extent.