title: The pharmacokinetics and effects on blood pressure of multiple doses of the novel anti-migraine drug zolmitriptan (311C90) in healthy volunteers.
abstract: OBJECTIVE
  Zolmitriptan (311C90), a novel, selective, centrally and peripherally acting 5-HT1D-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 CLR. 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 CLR. 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.
authors.affiliation: Glaxo Wellcome Research & Development, Greenford, Middlesex.
authors.forename: R
authors.initials: R
authors.lastname: Dixon
authors.forename: C
authors.initials: C
authors.lastname: Gillotin
authors.forename: M
authors.initials: M
authors.lastname: Gibbens
authors.forename: J
authors.initials: J
authors.lastname: Posner
authors.forename: R W
authors.initials: RW
authors.lastname: Peck
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D001794:Blood Pressure / Q000187:drug effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000188:drug therapy / Q000378:metabolism*; D010080:Oxazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D023303:Oxazolidinones; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D014363:Tryptamines
chemical_list: D010080:Oxazoles; D023303:Oxazolidinones; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C089750:zolmitriptan