No need to adjust the dose of 311C90 (zolmitriptan), a novel anti-migraine treatment, in patients with renal failure not requiring dialysis.
311C90 ("Zomig", zolmitriptan), is a novel and selective, centrally and peripherally acting 5 HT1B/1D receptor agonist in development for the acute, oral treatment of migraine. We have conducted a parallel group study in patients with moderate/severe renal impairment (creatinine clearance < or = 40 ml/min) and age- and sex-matched healthy volunteers (creatinine clearance > or = 60 ml/min). All subjects received a single, 10 mg dose of 311C90. Mean peak concentrations of 311C90 and its pharmacologically active N-desmethyl metabolite (183C91) were similar in both groups although AUC0-infinity for 183C91 was increased by 35% in the renally impaired patients. Other pharmacokinetic parameters were little changed apart from the expected reduction in CLR and urinary recovery and a small increase of 0.9 and 1.0 h, respectively, in the mean half-lives of 311C90 and 183C91. For the 2 inactive metabolites, the N-oxide (1652W92) and the indolacetic acid (2161W92), mean peak concentrations were approximately 3 times higher in renally impaired patients than in healthy volunteers and AUC0-infinity was 6-7.5 times higher. CLR for these metabolites was approximately 90% lower in renal impairment and half-life of both was increased approximately 3-fold. Baseline blood pressures were higher in the renally impaired group. After 311C90 there was a transient, small increase in blood pressure in both groups. There was little difference in the increase in diastolic blood pressure between the groups (16 mmHg in both) but the rise in systolic blood pressure was greater in the renally impaired group (23 mmHg vs 16 mmHg in healthy subjects). The lack of substantial changes in the plasma concentrations of both parent compound and 183C91, and the similarity of the changes in blood pressure, in renally impaired subjects compared to healthy volunteers suggest that there is no reason to adjust the dose of 311C90 in patients with renal impairment.
Gillotin
C
C
Department of Clinical Pharmacology, Laboratoire Glaxo Wellcome, Issy-les-Moulineaux, France.
Bagnis
C
C
Mamet
J P
JP
Peck
R W
RW
Deray
G
G
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006207:Half-Life; D006801:Humans; D007676:Kidney Failure, Chronic / Q000378:metabolism* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000188:drug therapy*; D010080:Oxazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D023303:Oxazolidinones; D006435:Renal Dialysis; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D014363:Tryptamines
D010080:Oxazoles; D023303:Oxazolidinones; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C089750:zolmitriptan