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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

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Abstract

Background and objective: Bortezomib, an antineoplastic for the treatment of relapsed multiple myeloma and mantle cell lymphoma, undergoes metabolism through oxidative deboronation by cytochrome P450 (CYP) enzymes, primarily CYP3A4 and CYP2C19. Omeprazole, a proton-pump inhibitor, is primarily metabolized by and demonstrates high affinity for CYP2C19. This study investigated whether coadministration of omeprazole affected the pharmacokinetics, pharmacodynamics and safety profile of bortezomib in patients with advanced cancer. The variability of bortezomib pharmacokinetics with CYP enzyme polymorphism was also investigated.

Patients and methods: This open-label, crossover, pharmacokinetic drug-drug interaction study was conducted at seven institutions in the US and Europe between January 2005 and August 2006. Patients who had advanced solid tumours, non-Hodgkin’s lymphoma or multiple myeloma, were aged ≥18 years, weighed ≥50 kg and had a life expectancy of ≥3 months were eligible. Patients received bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 for two 21-day cycles, plus omeprazole 40 mg in the morning of days 6–10 and in the evening of day 8 in either cycle 1 (sequence 1) or cycle 2 (sequence 2). On day 21 of cycle 2, patients benefiting from therapy could continue to receive bortezomib for six additional cycles. Blood samples for pharmacokinetic/ pharmacodynamic evaluation were collected prior to and at various timepoints after bortezomib administration on day 8 of cycles 1 and 2. Blood samples for pharmacogenomics were also collected. Pharmacokinetic parameters were calculated by noncompartmental analysis of plasma concentration-time data for bortezomib administration on day 8 of cycles 1 and 2, using WinNonlin™ version 4.0. 1.a software. The pharmacodynamic profile was assessed using a whole-blood 20S proteasome inhibition assay.

Results: Twenty-seven patients (median age 64 years) were enrolled, 12 in sequence 1 and 15 in sequence 2, including eight and nine pharmacokinetic-evaluable patients, respectively. Bortezomib pharmacokinetic parameters were similar when bortezomib was administered alone or with omeprazole (maximum plasma concentration 120 vs 123 ng/mL; area under the plasma concentration-time curve from 0 to 72 hours 129 vs 135 ng · h/mL). The pharmacodynamic parameters were also similar (maximum effect 85.8% vs 93.7%; area under the percent inhibition-time curve over 72 hours 4052 vs 3910 % × h); the differences were not statistically significant. Pharmacogenomic analysis revealed no meaningful relationships between CYP enzyme polymorphisms and pharmacokinetic/pharmacodynamic parameters. Toxicities were generally similar between patients in sequence 1 and sequence 2, and between cycle 1 and cycle 2 in both treatment sequences. Among 26 evaluable patients, 13 (50%) were assessed as benefiting from bortezomib at the end of cycle 2 and continued to receive treatment.

Conclusions: No impact on the pharmacokinetics, pharmacodynamics and safety profile of bortezomib was seen with coadministration of omeprazole. Concomitant administration of bortezomib and omeprazole is unlikely to cause clinically significant drug-drug interactions and is unlikely to have an impact on the efficacy or safety of bortezomib.

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Acknowledgements

The authors acknowledge Johnson & Johnson Pharmaceutical Research and Development, LLC (Raritan, NJ, USA), for providing funding for this study, and also acknowledge the Johnson & Johnson Pharmaceutical Research and Development Pharmacogenomics Team, including members from the Departments of Pharmacogenomics and Biostatistics. Milin Acharya, Kai Chan and Nadine Cohen are employees of Johnson & Johnson Pharmaceutical Research and Development, LLC. David Quinn, John Nemunaitis, Carolyn Britten and Assen Dudov have received funding from Johnson & Johnson Pharmaceutical Research and Development, LLC, to conduct this trial. David Quinn is on the Speakers Bureau for Millennium Pharmaceuticals, Inc. (Cambridge, MA, USA). Jyotsna Fuloria, Nashat Gabrail and Lorrin Yee have no conflicts of interest that are directly relevant to the content of this study.

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Authors and Affiliations

  1. University of Southern California, Los Angeles, California, USA

    David I. Quinn

  2. Mary Crowley Medical Research Center, Dallas, Texas, USA

    John Nemunaitis

  3. Oschner Cancer Institute, New Orleans, Louisiana, USA

    Jyotsna Fuloria

  4. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA

    Carolyn D. Britten

  5. Gabrail Cancer Center, Canton, Ohio, USA

    Nashat Gabrail

  6. Northwest Medical Specialties, Tacoma, Washington, USA

    Lorrin Yee

  7. Johnson & Johnson, LLC, Raritan, New Jersey, USA

    Milin Acharya & Nadine Cohen

  8. Johnson & Johnson, LLC, High Wycombe, Buckinghamshire, UK

    Kai Chan

  9. Sofia Cancer Centre, Sofia, Bulgaria

    Assen Dudov

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  1. David I. Quinn
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Quinn, D.I., 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 48, 199–209 (2009). https://doi.org/10.2165/00003088-200948030-00006

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