The pharmacokinetics and effects on blood pressure of multiple doses of the novel anti‐migraine drug zolmitriptan (311C90) in healthy volunteers

Abstract

Aims Zolmitriptan (311C90), a novel, selective, centrally and peripherally acting 5-HT 1D -receptor agonist is under development as an acute treatment for migraine. The tolerability, pharmacokinetics and effects on blood pressure and heart rate of multiple doses of 5 or 10 mg (5 doses administered over 24 h) were compared, in healthy adult volunteers, with those after placebo and single doses of zolmitriptan. Methods Twelve subjects participated in a randomized, balanced, crossover comparison. Plasma and urine concentrations of zolmitriptan and its metabolites, pulse rate and blood pressure were measured at intervals after drug. Ten volunteers completed the study. Results Zolmitriptan was well tolerated after single and multiple doses throughout the study. There was no evidence of significant changes in the pharmacokinetic parameters of zomitriptan or its metabolites after the last dose compared to the first, except for an expected rise in peak concentrations and a small, apparent increase in the amount of drug excreted in urine and hence in CL R . After the last 10 mg dose, mean dosing interval zolmitriptan AUC was 80.3 ng ml −1 h compared with 86.5 ng ml −1 h after the single 10 mg dose (95% CI for ratio 0.76-1.13). There was no evidence of changes in the pharmacokinetic parameters of zolmitriptan and its metabolites after 10 mg compared with 5 mg, except a small increase in zolmitriptan CL R . There were no statistically significant increases in peak systolic or diastolic blood pressure after the last doses of zolmitriptan compared to placebo or in peak blood pressure after the last dose compared to the first. There were no significant differences between blood pressure immediately before the first and last doses of each multiple dose regimen. Peak erect systolic blood pressure after the last 10 mg dose (137 mmHg ) was significantly lower than that after placebo (147 mmHg, 95% CI for difference −18, −2) and that after the last 5 mg dose (148 mmHg, 95% CI −19, −3). Conclusions Repeated doses of 5 or 10 mg zolmitriptan are well tolerated despite higher plasma concentrations than expected from single doses.

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

“…The lower limit of quantification (LOQ) was 0.1 ng/ ml for zolmitriptan and 0.2 ng/ml for 183C91. Urinary concentrations of zolmitriptan, 183C91, 2161W92 and 1652W92 were determined using HPLC with fluorescence detection, with LOQs of 100 ng/ml for each analyte [13]. Quality control samples were included in the analytical runs used to measure zolmitriptan and its metabolites in plasma and urine.…”

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

“…62) (Jandu et al, 2001). Following oral administration, the metabolite circulates at about half the level of the parent drug (Dixon et al, 1997;Peck et al, 1998), thus it can be projected that the contributions of zolmitriptan and the N-desmethyl metabolite are about equal.…”

The triptans

“…Coadministration of propranolol resulted in a 56% increase in the area under the plasma concentration-time curve of zolmitriptan [74]. With a dose of zolmitriptan 2.5 mg no additional side effects were seen when combined with propranolol.…”