title: 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.
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
  The aim of this study was to assess the effect of concomitant administration of ketoconazole on the pharmacokinetics (PK) and pharmacodynamics (PD) of bortezomib.
  
  
  METHODS
  This was a prospective, multicenter, open-label, randomized, multiple-dose, 2-way crossover study in patients with advanced solid tumors. All patients received bortezomib 1.0 mg/m(2) IV (on days 1, 4, 8, and 11 of two 21-day cycles) and were randomized to receive concomitant ketoconazole 400 mg on days 6, 7, 8, and 9 of cycle 1 or 2. Serial blood samples were collected over the day-8 dosing interval (immediately prior to bortezomib administration, and from 5 minutes to 72 hours after administration) in cycles 1 and 2 for measurement of plasma bortezomib concentrations for noncompartmental PK analysis and blood 20S proteasome inhibition for PD analysis. All adverse events (AEs) were recorded during each cycle including serious AEs and all neurotoxicity events for up to 30 days after the last dose of bortezomib.
  
  
  RESULTS
  Twenty-one patients (median age, 57 years; sex, 67% male; race, 86% white; median body surface area, 2.01 m(2)) were randomized to treatment. Twelve patients completed the protocol-specified dosing and PK sampling in both cycles 1 and 2. Assessment of the effect of ketoconazole on bortezomib PK and PD was based on data in these 12 PK-evaluable patients. The ratio of geometric mean bortezomib AUC(0-tlast)(AUC from time 0 to last quantifiable concentration) for bortezomib plus ketoconazole versus bortezomib alone was 1.352 (90% CI, 1.032-1.772). Consistent with this observed mean increase in bortezomib exposure, concomitant administration of ketoconazole was associated with a corresponding increase (24%-46%) in the blood proteasome inhibitory effect.
  
  
  CONCLUSIONS
  Concomitant administration of the CYP3A inhibitor ketoconazole with bortezomib resulted in a mean increase of 35% in bortezomib exposure. ClinicalTrials.gov identifier: NCT00129207.
authors.affiliation: Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA. karthik.venkatakrishnan@mpi.com
authors.forename: Karthik
authors.initials: K
authors.lastname: Venkatakrishnan
authors.forename: Michael
authors.initials: M
authors.lastname: Rader
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: Suresh
authors.initials: S
authors.lastname: Ramalingam
authors.forename: Eric
authors.initials: E
authors.lastname: Chen
authors.forename: William
authors.initials: W
authors.lastname: Riordan
authors.forename: William
authors.initials: W
authors.lastname: Trepicchio
authors.forename: Michael
authors.initials: M
authors.lastname: Cooper
authors.forename: Michael
authors.initials: M
authors.lastname: Karol
authors.forename: Lisa
authors.initials: L
authors.lastname: von Moltke
authors.forename: Rachel
authors.initials: R
authors.lastname: Neuwirth
authors.forename: Merrill
authors.initials: M
authors.lastname: Egorin
authors.forename: Gurkamal
authors.initials: G
authors.lastname: Chatta
mesh_terms: D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D019540:Area Under Curve; D001897:Boronic Acids / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D018592:Cross-Over Studies; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011446:Prospective Studies; D011719:Pyrazines / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000935:Antifungal Agents; D000970:Antineoplastic Agents; D001897:Boronic Acids; D065692:Cytochrome P-450 CYP3A Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D007654:Ketoconazole