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

https://doi.org/10.1016/j.clinthera.2009.11.012Get rights and content

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, openlabel, randomized, multiple-dose, 2-way crossover study in patients with advanced solid tumors. All patients received bortezomib 1.0 mg/m2 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 m2) were randomized to treatment. Twelve pa- tients 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 AUC0-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.

Conclusion: Concomitant administration of the CYP3A inhibitor ketoconazole with bortezomib resulted in a mean increase of 35% in bortezomib exposure. ClinicalTrials.gov identifier: NCT00129207.

References (51)

  • PM Voorhees et al.

    The proteasome as a target for cancer therapy

    Clin Cancer Res.

    (2003)
  • YH Ling et al.

    PS-341, a novel proteasome inhibitor, induces Bcl-2 phosphorylation and cleavage in association with G2-M phase arrest and apoptosis

    Mol Cancer Ther.

    (2002)
  • J Adams et al.

    Proteasome inhibitors: A novel class of potent and effective antitumor agents

    Cancer Res.

    (1999)
  • SA Shah et al.

    26S Proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer

    J Cell Biochem.

    (2001)
  • S Jagannath et al.

    A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma

    Br J Haematol.

    (2004)
  • PG Richardson et al.

    A phase 2 study of bortezomib in relapsed, refractory myeloma

    N Engl J Med.

    (2003)
  • RI Fisher et al.

    Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma

    J Clin Oncol.

    (2006)
  • PG Richardson et al.

    Bortezomib or high-dose dexamethasone for relapsed multiple myeloma

    N Engl J Med.

    (2005)
  • JF San Miguel et al.

    MMY-3002: A phase 3 study comparing bortezomib-melphalan-prednisone (VMP) with melphalan-prednisone (MP) in newly diagnosed multiple myeloma. ASH Annual Meeting Abstracts

    Blood.

    (2007)
  • C Aghajanian et al.

    A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies

    Clin Cancer Res.

    (2002)
  • CN Papandreou et al.

    Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgenindependent prostate cancer

    J Clin Oncol.

    (2004)
  • C Aghajanian et al.

    Phase I trial of bortezomib and carboplatin in recurrent ovarian or primary peritoneal cancer

    J Clin Oncol.

    (2005)
  • WA Messersmith et al.

    Phase I trial of bortezomib in combination with docetaxel in patients with advanced solid tumors

    Clin Cancer Res.

    (2006)
  • DP Ryan et al.

    A Phase I study of bortezomib plus irinotecan in patients with advanced solid tumors

    Cancer.

    (2006)
  • DP Ryan et al.

    Phase I clinical trial of bortezomib in combination with gemcitabine in patients with advanced solid tumors

    Cancer.

    (2006)
  • Cited by (59)

    • A simplified method for bortezomib determination using dried blood spots in combination with liquid chromatography/tandem mass spectrometry

      2021, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
    • Pharmacology differences among proteasome inhibitors: Implications for their use in clinical practice

      2021, Pharmacological Research
      Citation Excerpt :

      These combinations should be therefore avoided, or the dose of bortezomib adjusted and patients monitored for efficacy [54,55]. Ketoconazole was found to increase bortezomib exposure by 35% and patients taking bortezomib with potent CYP3A inhibitors should be monitored for ADRs [55,56]. Patients receiving bortezomib plus ciclosporin should also be monitored for symptoms of neuropathy and the treatment schedule should be re-evaluated in the case of worsening of peripheral neuropathy [55].

    View all citing articles on Scopus
    *

    Current affiliation: Translational Genomics Research Institute, Scottsdale, Arizona.

    Current affiliation: Emory University School of Medicine, Winship Cancer Institute, Atlanta, Georgia.

    View full text