Effect of ketoconazole administration on the pharmacokinetics (PK) and pharmacodynamics (PD) of bortezomib in patients with advanced solid tumors

13016 Background: Bortezomib (btz; VELCADE) is a first-in-class small molecule proteasome inhibitor used to treat patients with multiple myeloma and mantle cell lymphoma. In vitro and in vivo studies indicate that btz is primarily metabolized by CYP3A4 and CYP2C19. We conducted a study to evaluate the effect of inhibition of CYP3A4 with ketoconazole (keto) on the PK of btz in humans. Methods: The study enrolled patients with advanced malignancies for whom standard therapy was not available. Patients received btz 1.0mg/m2 (IV) on days 1, 4, 8, and 11 of a 21-day cycle, and were randomized to receive keto 400mg (PO) on days 6, 7, 8, and 9 of either the first or second cycle of treatment. Blood samples for plasma btz determination were collected over 72 hours following the Day 8 dose in Cycles 1 and 2. PK parameters were computed non-compartmentally. PD parameters were derived from an Emax model of percentage proteasome inhibition in whole blood. Results: Of the 21 patients enrolled, 13 had sufficient PK sam...