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Interaction between Ketoconazole and Almotriptan in Healthy Volunteers

From the Clinical Pharmacology Unit, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan.

The interaction between almotriptan, a 5-HT_1B/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 C_max 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.

Key Words: Migraine • serotonin receptor agonist • pharmacokinetics • CYP3A4

Address for reprints: Joseph C. Fleishaker, PhD, Clinical Pharmacology Unit, 7215-24-205, Pharmacia & Upjohn, Inc., 301 Henrietta Street, Kalamazoo, MI 49007.

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