The tolerability and pharmacokinetics of the novel antimigraine compound 311C90 in healthy male volunteers.
1. 311C90 is a novel and selective agonist at 5-HT1D receptors, with central and peripheral actions, currently in development for the acute oral treatment of migraine. 2. The pharmacokinetic and tolerability profiles of single oral doses from 1-50 mg 311C90 were investigated in 12 healthy male volunteers in a double-blind, placebo-controlled, dose-escalating study. 3. 311C90 was well tolerated with most adverse experiences of mild and transient nature. 4. Absorption was rapid with dose-independent kinetics. Median tmax was 2-4 h although 50-85% of eventual Cmax was attained within 1 h. The t1/2 was 2.5-3 h with a high apparent plasma clearance (CL/F > 2000 ml min-1) and apparent volume of distribution (Vz/F) of 400-500 l. 5. Three metabolites were detected in plasma and urine, one of which, the N-desmethyl metabolite, has 5-HT1D agonist activity. 6. 311C90 showed no clinically significant effects on blood pressure, heart rate, ECG or laboratory variables at any dose and demonstrated a tolerability and pharmacokinetic profile compatible with an acute oral migraine treatment.
Seaber
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Department of Clinical Pharmacology, Glaxo Wellcome, Beckenham, Kent, UK.
On
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Phillips
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Churchus
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Posner
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Rolan
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D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000188:drug therapy*; D010080:Oxazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D023303:Oxazolidinones; D010919:Placebos; D012016:Reference Values; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D014363:Tryptamines
D010080:Oxazoles; D023303:Oxazolidinones; D010919:Placebos; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C089750:zolmitriptan