title: Blood concentrations of everolimus are markedly increased by ketoconazole.
abstract: The authors sought to quantify the influence of the CYP3A and P-glycoprotein inhibitor ketoconazole on the pharmacokinetics of everolimus in healthy subjects. This was a 2-period, single-sequence, crossover study in 12 healthy subjects. In period 1, subjects received the reference treatment of a single 2-mg dose of everolimus. In period 2, they received the test treatment of ketoconazole 200 mg twice daily for a total of 8 days and a single dose of everolimus coadministered on the fourth day of ketoconazole therapy. The test/reference ratio and 90% confidence interval were derived for everolimus maximum concentration and area under the curve. During ketoconazole coadministration, everolimus maximum concentration increased 3.9-fold (90% confidence interval, 3.4-4.6) from 15 +/- 4 ng/mL to 59 +/- 13 ng/mL. Everolimus area under the curve increased 15.0-fold (90% confidence interval, 13.6-16.6) from 90 +/- 23 ng*h/mL to 1324 +/- 232 ng*h/mL. Everolimus half-life was prolonged by 1.9-fold from 30 +/- 4 hours to 56 +/- 5 hours. Everolimus did not appear to alter ketoconazole predose concentrations. Given the magnitude of this drug interaction, use of ketoconazole should be avoided if possible in everolimus-treated patients.
authors.affiliation: Novartis Pharma, Building WSJ 27.P081, 4002 Basel, Switzerland.
authors.forename: J M
authors.initials: JM
authors.lastname: Kovarik
authors.forename: D
authors.initials: D
authors.lastname: Beyer
authors.forename: M N
authors.initials: MN
authors.lastname: Bizot
authors.forename: Q
authors.initials: Q
authors.lastname: Jiang
authors.forename: M
authors.initials: M
authors.lastname: Shenouda
authors.forename: R L
authors.initials: RL
authors.lastname: Schmouder
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000494:pharmacology*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004357:Drug Synergism; D000068338:Everolimus; D005260:Female; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood* / Q000493:pharmacokinetics; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics
chemical_list: D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D000068338:Everolimus; D007654:Ketoconazole; D020123:Sirolimus