Interaction between ketoconazole and almotriptan in healthy volunteers.
The interaction between almotriptan, a 5-HT1B/1D agonist, and the potent CYP3A4 inhibitor ketoconazole was examined in 16 healthy volunteers. Subjects received (A) 12.5 mg almotriptan orally on Day 2 of a 3-day regimen of 400 mg ketoconazole once daily and (B) 12.5 mg almotriptan in a crossover design. Plasma and urine concentrations of almotriptan were measured by HPLC. Treatment effects on almotriptan pharmacokinetics were assessed by analysis of variance. Ketoconazole coadministration increased mean almotriptan AUC and Cmax from 312 to 490 ng h/mL and 52.6 to 84.5 ng/mL, respectively. Mean oral clearance was decreased from 40.7 to 26.2 L/h by ketoconazole, with an accompanying increase in the fraction of almotriptan excreted unchanged in the urine (40.6% to 53.3%) and a decrease in renal clearance (16.4 to 13.8 L/h). These effects were statistically significant. The effects of ketoconazole on almotriptan clearance were consistent with inhibition of the CYP3A4-mediated metabolism and a slight effect on the active tubular secretion of almotriptan.
Clinical Pharmacology Unit, 7215-24-205, Pharmacia & Upjohn, Inc., 301 Henrietta Street, Kalamazoo, MI 49007, USA.
Joseph C
JC
Fleishaker
Beth D
BD
Herman
Barbara J
BJ
Carel
Nkechi E
NE
Azie
D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics*; D007654:Ketoconazole / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000097:blood / Q000493:pharmacokinetics*; D014363:Tryptamines
D000935:Antifungal Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; C470302:HTR1B protein, human; D007211:Indoles; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C409045:almotriptan; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole