Effect of the CYP3A inhibitor ketoconazole on the pharmacokinetics and pharmacodynamics of bortezomib in patients with advanced solid tumors: a prospective, multicenter, open-label, randomized, two-way crossover drug-drug interaction study.

摘要: Abstract Background: The proteasome inhibitor bortezomib undergoes oxidative biotransformation via multiple cytochrome P450 (CYP) enzymes, with CYP3A4 identified as a partial, yet potentially important, contributor based on in vitro drug metabolism studies. Objective: aim of this study was to assess the effect concomitant administration ketoconazole pharmacokinetics (PK) and pharmacodynamics (PD) bortezomib. Methods: This prospective, multicenter, openlabel, randomized, multiple-dose, 2-way crossover patients advanced solid tumors. All received 1.0 mg/m2 IV (on days 1, 4, 8, 11 two 21-day cycles) were randomized receive 400 mg 6, 7, 9 cycle 1 or 2. Serial blood samples collected over day-8 dosing interval (immediately prior administration, from 5 minutes 72 hours after administration) cycles 2 for measurement plasma concentrations noncompartmental PK analysis 20S inhibition PD analysis. adverse events (AEs) recorded during each including serious AEs all neurotoxicity up 30 last dose Results: Twenty-one (median age, 57 years; sex, 67% male; race, 86% white; median body surface area, 2.01 m2) treatment. Twelve pa- tients completed protocol-specified sampling both Assessment data these 12 PK-evaluable patients. ratio geometric mean AUC0-tlast(AUC time 0 quantifiable concentration) plus versus alone 1.352 (90% CI, 1.032–1.772). Consistent observed increase exposure, associated corresponding (24%–46%) inhibitory effect. Conclusion: Concomitant CYP3A resulted 35% exposure. ClinicalTrials.gov identifier: NCT00129207.