Skip to main content
Log in

Effect of Cytochrome P450 3A4 Inducers on the Pharmacokinetic, Pharmacodynamic and Safety Profiles of Bortezomib in Patients with Multiple Myeloma or Non-Hodgkin’s Lymphoma

Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objective: Bortezomib, an antineoplastic agent with proteasome inhibitory activity, is extensively metabolized by the hepatic microsomal cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C19. Drugs that affect these enzymes may therefore have an impact on the pharmacological profile of bortezomib. This study evaluated the effects of co-administration of a potent CYP3A4 inducer (rifampicin [rifampin]) and a weak CYP3A4 inducer (dexamethasone) on the pharmacokinetic, pharmacodynamic and safety profiles of bortezomib.

Patients and Methods: Patients aged ≥18 years with relapsed or refractory multiple myeloma or non-Hodgkin’s lymphoma received intravenous bortezomib 1.3 mg/m2, administered on days 1, 4, 8 and 11 of a 21-day cycle, for 3 cycles. In stage 1, patients were randomized (1:1) to receive bortezomib alone or in combination with oral rifampicin 600 mg once daily on days 4–10 during cycle 3 only. If the mean area under the plasma concentration-time curve (AUC) of bortezomib was reduced by ≥30% during rifampicin co-administration, then stage 2 was initiated, in which patients received bortezomib with dexamethasone 40 mg once daily on days 1–4 and days 9–12 during cycle 3 only. Blood samples were collected on days 11 through 14 of cycles 2 and 3 before and after bortezomib administration, at prespecified time points, for pharmacokinetic and pharmacodynamic (proteasome inhibition) assessments.

Results: Twelve patients in the bortezomib-alone arm, six patients in the bortezomib plus rifampicin arm and seven patients in the bortezomib plus dexamethasone arm were included in the pharmacokinetics-evaluable set. Rifampicin reduced the mean AUC from 0 to 72 hours (AUC72h) of bortezomib by approximately 45% (223 ng · h/mL in cycle 2 vs 123 ng · h/mL in cycle 3), while dexamethasone had no effect (mean AUC72h: 179 ng · h/mL in cycle 2 vs 170 ng · h/mL in cycle 3). Proteasome inhibition parameters in peripheral blood were unaffected by rifampicin or dexamethasone. Safety profiles were similar across the treatment arms and consistent with previous experience of bortezomib.

Conclusions: In patients with multiple myeloma or non-Hodgkin’s lymphoma, co-administration of rifampicin decreased the exposure to bortezomib but did not affect the proteasome inhibition or safety profiles; co-administration of dexamethasone did not affect the exposure to bortezomib, proteasome inhibition or safety profiles. Concomitant administration of bortezomib with strong CYP3A4 inducers such as rifampicin is not recommended, as it may result in a reduction of the clinical effect, whereas concomitant administration of weak CYP3A4 inducers such as dexamethasone does not affect the pharmacological profile of bortezomib.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Table I
Fig. 2
Table II
Fig. 3
Table III

Similar content being viewed by others

References

  1. Egger T, Dormann H, Ahne G, et al. Identification of adverse drug reactions in geriatric inpatients using a computerised drug database. Drugs Aging 2003; 20: 769–76

    Article  PubMed  CAS  Google Scholar 

  2. Sokol KC, Knudsen JF, Li MM. Polypharmacy in older oncology patients and the need for an interdisciplinary approach to side-effect management. J Clin Pharm Ther 2007; 32: 169–75

    Article  PubMed  CAS  Google Scholar 

  3. McLeod HL. Clinically relevant drug-drug interactions in oncology. Br J Clin Pharmacol 1998; 45: 539–44

    Article  PubMed  CAS  Google Scholar 

  4. Adams J, Palombella VJ, Sausville EA, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 1999; 59: 2615–22

    PubMed  CAS  Google Scholar 

  5. de Vos S, Goy A, Dakhil SR, et al. Multicenter randomized phase II study of weekly or twice-weekly bortezomib plus rituximab in patients with relapsed or refractory follicular or marginal-zone B-cell lymphoma. J Clin Oncol 2009; 27: 5023–30

    Article  PubMed  Google Scholar 

  6. Dunleavy K, Pittaluga S, Czuczman MS, et al. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood 2009; 113: 6069–76

    Article  PubMed  CAS  Google Scholar 

  7. Coiffier B, Osmanov E, Hong X, et al. A phase 3 trial comparing bortezomib plus rituximab with rituximab alone in patients with relapsed or refractory, rituximab-naive or -sensitive, follicular lymphoma [abstract]. 52nd Annual Meeting and Exposition, American Society of Hematology; 2010 Dec 4–7; Orlando (FL)

    Google Scholar 

  8. Uttamsingh V, Lu C, Miwa G, et al. Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the hepatic metabolism of the proteasome inhibitor bortezomib. Drug Metab Dispos 2005; 33: 1723–8

    Article  PubMed  CAS  Google Scholar 

  9. Venkatakrishnan K, Rader M, Ramanathan RK, et al. 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. Clin Ther 2009; 31: 2444–58

    Article  PubMed  CAS  Google Scholar 

  10. Quinn DI, Nemunaitis J, Fuloria J, et al. Effect of the cytochrome P450 2C19 inhibitor omeprazole on the pharmacokinetics and safety profile of bortezomib in patients with advanced solid tumours, non-Hodgkin’s lymphoma or multiple myeloma. Clin Pharmacokinet 2009; 48: 199–209

    Article  PubMed  CAS  Google Scholar 

  11. US FDA. Drug development and drug interactions: table of substrates, inhibitors and inducers [online]. Available from URL: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm [Accessed 2011 Sep 27]

  12. Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol 2010; 28: 4621–9

    Article  PubMed  CAS  Google Scholar 

  13. Kropff MH, Bisping G, Wenning D, et al. Bortezomib in combination with dexamethasone for relapsed multiple myeloma. Leuk Res 2005; 29: 587–90

    Article  PubMed  CAS  Google Scholar 

  14. Minnema MC, van der Spek E, van de Donk NW, et al. New developments in the treatment of patients with multiple myeloma. Neth J Med 2010; 68: 24–32

    PubMed  CAS  Google Scholar 

  15. Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In: Macleod CM, editor. Evaluation of chemotherapeutic agents. New York: Columbia University Press, 1949: 199–205

    Google Scholar 

  16. National Cancer Institute. Common terminology criteria for adverse events v3.0 (CTCAE) [online]. Available from URL: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf [Accessed 2011 Oct 3]

  17. Lightcap ES, McCormack TA, Pien CS, et al. Proteasome inhibition measurements: clinical application. Clin Chem 2000; 46: 673–83

    PubMed  CAS  Google Scholar 

  18. Blade J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 1998; 102: 1115–23

    Article  PubMed  CAS  Google Scholar 

  19. Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 1999; 17: 1244

    PubMed  CAS  Google Scholar 

  20. Huang SM, Temple R, Throckmorton DC, et al. Drug interaction studies: study design, data analysis, and implications for dosing and labeling. Clin Pharmacol Ther 2007; 81: 298–304

    Article  PubMed  CAS  Google Scholar 

  21. Backman JT, Olkkola KT, Neuvonen PJ. Rifampin drastically reduces plasma concentrations and effects of oral midazolam. Clin Pharmacol Ther 1996; 59: 7–13

    Article  PubMed  CAS  Google Scholar 

  22. Nassr N, Huennemeyer A, Herzog R, et al. Effects of rifampicin on the pharmacokinetics of roflumilast and roflumilast N-oxide in healthy subjects. Br J Clin Pharmacol 2009; 68: 580–7

    Article  PubMed  CAS  Google Scholar 

  23. Harousseau JL, Attal M, Leleu X, et al. Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study. Haematologica 2006; 91: 1498–505

    PubMed  CAS  Google Scholar 

  24. Delforge M, Blade J, Dimopoulos MA, et al. Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues. Lancet Oncol 2010; 11: 1086–95

    Article  PubMed  CAS  Google Scholar 

  25. Phuphanich S, Supko JG, Carson KA, et al. Phase 1 clinical trial of bortezomib in adults with recurrent malignant glioma. J Neurooncol 2010; 100: 95–103

    Article  PubMed  CAS  Google Scholar 

  26. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352: 2487–98

    Article  PubMed  CAS  Google Scholar 

  27. Jagannath S, Barlogie B, Berenson J, et al. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 2004; 127: 165–72

    Article  PubMed  CAS  Google Scholar 

  28. Fisher RI, Bernstein SH, Kahl BS, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 2006; 24: 4867–74

    Article  PubMed  Google Scholar 

  29. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348: 2609–17

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors acknowledge Dr Lydia Dreosti (University of the Free State, Bloemfontein, Free State, South Africa) who was an investigator in this study, Dr Petra Vinken (Johnson & Johnson Pharmaceutical Research & Development, Division of Janssen Pharmaceutica NV, Beerse, Belgium) for assistance in proteasome analysis, Dr Vera Hillewaert (Johnson & Johnson Pharmaceutical Research & Development, Division of Janssen Pharmaceutica NV) for assistance in bortezomib analysis and Ms Priya Ramaswami (Johnson & Johnson Pharmaceutical Research & Development, LLC, Raritan, NJ, USA) for programming support. The authors also thank Drs Michal Szymczyk, Beata Ostrowska, Joanna Romejko-Jarosinska and Ewa Paszkiewicz-Kozik (Maria Sklodowska-Curie Memorial Institute and Oncology Centre, Warsaw, Poland); Drs M.J. Webb and C.L. Barrett (University of the Free State); Ms Becky Reddell-Denton and Ms Nicola Crosbie (Plymouth Hospitals NHS Trust, Plymouth, UK); and Ms Karin Forti and Ms Marina Reidler (Rabin Medical Center, Petach-Tikva, Israel) for their assistance during the conduct of the study. Dr Sarika Shirke (SIRO Clinpharm Pvt. Ltd., Thane, India) provided writing assistance, and Dr Namit Ghildyal (Johnson & Johnson Pharmaceutical Research & Development, LLC) provided additional editorial support for this manuscript. The authors are also thankful to the study participants, without whom this study would never have been accomplished.

Drs Feng, van de Velde, Patel and Girgis and Ms Skee are employees of Johnson & Johnson Pharmaceutical Research & Development, LLC. Drs van de Velde and Patel have equity holdings in Johnson & Johnson. Professor Hellmann and Drs Rule, Walewski, Shpilberg and Louw were investigators in this study. Professor Hellmann has received research funding from Johnson & Johnson Pharmaceutical Research & Development, LLC. Dr Rule has acted as an advisor and has received research funding from Johnson & Johnson Pharmaceutical Research & Development, LLC. Dr Walewski has received research funding and honoraria from Johnson & Johnson Pharmaceutical Research & Development, LLC, and Roche. Dr Shpilberg is a consultant and advisory board member for Johnson & Johnson Pharmaceutical Research & Development, LLC, and has received honoraria from Johnson & Johnson Pharmaceutical Research & Development, LLC. Dr Louw is a consultant for Johnson & Johnson Pharmaceutical Research & Development, LLC, Novartis and Key Oncologics; has received research funding from Novartis; has received honoraria from Johnson & Johnson Pharmaceutical Research & Development, LLC, Novartis and Key Oncologics; and is an advisory board member for Johnson & Johnson Pharmaceutical Research & Development, LLC, Novartis and Key Oncologics. He has received honoraria for speaking engagements and consultancy for Johnson & Johnson Pharmaceutical Research & Development, LLC.

All authors met the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this article, and all individuals who fulfilled those criteria are listed as authors. All authors had access to the study data, made the final decision about where to publish the data and approved submission of the manuscript to this journal.

This study was funded by Johnson & Johnson Pharmaceutical Research & Development, LLC, and Millennium Pharmaceuticals, Inc. (Cambridge, MA, USA).

Data from this study were presented at the 52nd Annual Meeting and Exposition of the American Society of Hematology (Orlando, FL, USA; December 4–7, 2010).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Andrzej Hellmann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hellmann, A., Rule, S., Walewski, J. et al. Effect of Cytochrome P450 3A4 Inducers on the Pharmacokinetic, Pharmacodynamic and Safety Profiles of Bortezomib in Patients with Multiple Myeloma or Non-Hodgkin’s Lymphoma. Clin Pharmacokinet 50, 781–791 (2011). https://doi.org/10.2165/11594410-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11594410-000000000-00000

Keywords

Navigation