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

Abstract

Aims Zolmitriptan (Zomig (formerly 311C90)) is a novel 5-HT 1B/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 doseproportionality 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. C max and AUC of oral zolmitriptan were dose-proportional 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 bioavailability in healthy volunteers and has dose-proportional pharmacokinetics that are not affected by food to any clinically relevant extent.Keywords: bioavailability, food, pharmacokinetics, zolmitriptan from 6 to 50 mg in healthy volunteers have already been Introduction described [9]. The absolute bioavailability of a single 10 mg dose is 49% [10], compared with 14% reported for Zolmitriptan (Zomig, formerly 311C90) is a new 5-hydroxytryptamine (5-HT) 1B/1D receptor agonist [1] sumatriptan 100 mg [11]. Zolmitriptan is rapidly absorbed after oral administration but as plasma profiles show multiple developed for the acute oral treatment of migraine. Clinical studies have shown it to be effective and well tolerated in peaks in some subjects, individual t max values may vary from 0.5 to 5 h [6]. Zolmitriptan is eliminated mainly by the acute treatment of migraine at doses of 2.5-25 mg, with a headache respo...

The pharmacokinetics of the antimigraine compound zolmitriptan in Japanese and Caucasian subjects

“…Geometric mean plasma concentration-time profiles for zolmitriptan in Japanese male and female volunteers to differences in body weight. The gender difference noted in Japanese subjects was similar to that previously reported in Caucasian populations (AUC and C max approximately 20% higher in females) [1]; however, the lack of clinical relevance of this finding is demonstrated by the fact that zolmitriptan is equally effective in both genders [16], and there is no evidence that females have a higher incidence of adverse events [15]. Overall, it is therefore unlikely that differences in pharmacokinetic parameters between Japanese and Caucasian subjects will translate into differences in the degree of effectiveness and safety associated with zolmitriptan in the two populations.…”

“…The pharmacokinetics of zolmitriptan have been characterised in studies undertaken in a predominantly Caucasian population. Zolmitriptan is rapidly absorbed when given as oral tablets both in the fasting state and when given with food [1]. Plasma concentrations reach 75% of maximum plasma concentration (C max ) within 1 h of administration and remain at or above this level for up to 6 h post-dose [2].…”

A Review of the Pharmacokinetics, Pharmacodynamics and Efficacy of Zolmitriptan in the Acute Abortive Treatment of Migraine

“…39,41,42 The half-life (t 1/2 ) was unchanged between the genders. These differences are thought to be due to the reduced fi rst-pass metabolism of the drug in women.…”

Multiple-dose pharmacokinetics of intranasally administered IS-159 in healthy subjects

“…It shouldbe mentioned that the present study was not powered to detect differences in gender. Higher plasma levels in females as compared to males have been reported for some other triptan drugs [24,25]. The magnitude of this effect was relatively small, was not judged to be clinically relevant and, as a consequence, has not led to dose adaptation in routine clinical practice.…”