Advertisement

Clinical Pharmacokinetics

, Volume 48, Issue 3, pp 199–209 | Cite as

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

  • David I. Quinn
  • John Nemunaitis
  • Jyotsna Fuloria
  • Carolyn D. Britten
  • Nashat Gabrail
  • Lorrin Yee
  • Milin Acharya
  • Kai Chan
  • Nadine Cohen
  • Assen Dudov
Original Research Article

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.

Keywords

Multiple Myeloma Omeprazole Bortezomib Mantle Cell Lymphoma Relapse Multiple Myeloma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

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.

References

  1. 1.
    Blume H, Donath F, Warnke A, et al. Pharmacokinetic drug interaction profiles of proton pump inhibitors. Drug Saf 2006; 29(9): 769–84PubMedCrossRefGoogle Scholar
  2. 2.
    Gerson LB, Triadafilopoulos G. Proton pump inhibitors and their drug interactions: an evidence-based approach. Eur J Gastroenterol Hepatol 2001 May; 13(5): 611–6PubMedCrossRefGoogle Scholar
  3. 3.
    McLeod HL. Clinically relevant drug-drug interactions in oncology. Br J Clin Pharmacol 1998 Jun; 45(6): 539–44PubMedCrossRefGoogle Scholar
  4. 4.
    Beijnen JH, Schellens JH. Drug interactions in oncology. Lancet Oncol 2004 Aug; 5(8): 489–96PubMedCrossRefGoogle Scholar
  5. 5.
    Blower P, De WR, Goodin S, et al. Drug-drug interactions in oncology: why are they important and can they be minimized? Crit Rev Oncol Hematol 2005 Aug; 55(2): 117–42PubMedCrossRefGoogle Scholar
  6. 6.
    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(10): 769–76PubMedCrossRefGoogle Scholar
  7. 7.
    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 Apr; 32(2): 169–75PubMedCrossRefGoogle Scholar
  8. 8.
    Janchawee B, Wongpoowarak W, Owatranporn T, et al. Pharmacoepidemiologic study of potential drug interactions in outpatients of a university hospital in Thailand. J Clin Pharm Ther 2005 Feb; 30(1): 13–20PubMedCrossRefGoogle Scholar
  9. 9.
    Thjodleifsson B. Treatment of acid-related diseases in the elderly with emphasis on the use of proton pump inhibitors. Drugs Aging 2002; 19(12): 911–27PubMedCrossRefGoogle Scholar
  10. 10.
    MacLeod SL, Nowell S, Massengill J, et al. Cancer therapy and polymorphisms of cytochromes P450. Clin Chem Lab Med 2000 Sep; 38(9): 883–87PubMedCrossRefGoogle Scholar
  11. 11.
    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(11): 1723–8PubMedCrossRefGoogle Scholar
  12. 12.
    Adams J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer 2004; 4(5): 349–60PubMedCrossRefGoogle Scholar
  13. 13.
    Voorhees PM, Dees EC, O’Neil B, et al. The proteasome as a target for cancer therapy. Clin Cancer Res 2003; 9(17): 6316–25PubMedGoogle Scholar
  14. 14.
    Aghajanian C, Soignet S, Dizon DS, et al. A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res 2002; 8(8): 2505–11PubMedGoogle Scholar
  15. 15.
    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 Sep; 24(30): 4867–74PubMedCrossRefGoogle Scholar
  16. 16.
    Goy A, Younes A, McLaughlin P, et al. Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin’s lymphoma. J Clin Oncol 2005; 23(4): 667–75PubMedCrossRefGoogle Scholar
  17. 17.
    O’Connor O, Wright J, Moskowitz C, et al. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. J Clin Oncol 2005; 23(4): 676–84PubMedCrossRefGoogle Scholar
  18. 18.
    Orlowski RZ, Stinchcombe TE, Mitchell BS, et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 2002; 20(22): 4420–7PubMedCrossRefGoogle Scholar
  19. 19.
    Papandreou CN, Daliani DD, Nix D, et al. Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol 2004; 22(11): 2108–21PubMedCrossRefGoogle Scholar
  20. 20.
    Richardson P, Sonneveld P, Schuster M, et al. Bortezomib continues to demonstrate superior efficacy compared with high-dose dexamethasone in relapsed multiple myeloma: updated results of the APEX trial [abstract]. Blood 2005; 106: 715aGoogle Scholar
  21. 21.
    Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352(24): 2487–98PubMedCrossRefGoogle Scholar
  22. 22.
    Fanucchi MP, Fossella FV, Belt R, et al. Randomized phase II study of bortezomib alone and bortezomib in combination with docetaxel in previously treated advanced non-small-cell lung cancer. J Clin Oncol 2006 Nov; 24(31): 5025–33PubMedCrossRefGoogle Scholar
  23. 23.
    Velcade® (bortezomib) for injection: US prescribing information. Cambridge (MA): Millennium Pharmaceuticals, Inc., 2006 DecGoogle Scholar
  24. 24.
    Ries LAG, Eisner MP, Kosary CL, et al. SEER cancer statistics review, 1975–2002 [online]. Available from URL: http://seer.cancer.gov/csr/1975_2002/ [Accessed 2006 Jun 15]
  25. 25.
    Lenz G, Dreyling M, Hiddemann W. Mantle cell lymphoma: established therapeutic options and future directions. Ann Hematol 2004; 83(2): 71–7PubMedCrossRefGoogle Scholar
  26. 26.
    Labutti J, Parsons I, Huang R, et al. Oxidative deboronation of the peptide boronic acid proteasome inhibitor bortezomib: contributions from reactive oxygen species in this novel cytochrome P450 reaction. Chem Res Toxicol 2006 Apr; 19(4): 539–46PubMedCrossRefGoogle Scholar
  27. 27.
    Pekol T, Daniels JS, Labutti J, et al. Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites. Drug Metab Dispos 2005; 33(6): 771–7PubMedCrossRefGoogle Scholar
  28. 28.
    Furuta T, Shirai N, Sugimoto M, et al. Influence of CYP2C19 pharmacogenetic polymorphism on proton pump inhibitor-based therapies. Drug Metab Pharmacokinet 2005 Jun; 20(3): 153–67PubMedCrossRefGoogle Scholar
  29. 29.
    Klotz U. Clinical impact of CYP2C19 polymorphism on the action of proton pump inhibitors: a review of a special problem. Int J Clin Pharmacol Ther 2006 Jul; 44(7): 297–302PubMedGoogle Scholar
  30. 30.
    Ko JW, Sukhova N, Thacker D, et al. Evaluation of omeprazole and lansoprazole as inhibitors of cytochrome P450 isoforms. Drug Metab Dispos 1997 Jul; 25(7): 853–62PubMedGoogle Scholar
  31. 31.
    Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16(1): 31–41PubMedCrossRefGoogle Scholar
  32. 32.
    US National Cancer Institute. Common terminology criteria for adverse events, v3.0 (CTCAE) [online]. Available from URL: http://ctep.cancer.gov/forms/CTCAEv3.pdf [Accessed 2008 Nov 26]
  33. 33.
    Lightcap ES, McCormack TA, Pien CS, et al. Proteasome inhibition measurements: clinical application. Clin Chem 2000; 46(5): 673–83PubMedGoogle Scholar
  34. 34.
    Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A 1977 Dec; 74(12): 5463–7PubMedCrossRefGoogle Scholar
  35. 35.
    Schaeffeler E, Schwab M, Eichelbaum M, et al. CYP2D6 genotyping strategy based on gene copy number determination by TaqMan real-time PCR. Hum Mutat 2003 Dec; 22(6): 476–85PubMedCrossRefGoogle Scholar
  36. 36.
    Watson DE, Li B. TaqMan applications in genetic and molecular toxicology. Int J Toxicol 2005 May; 24(3): 139–45PubMedCrossRefGoogle Scholar
  37. 37.
    Desta Z, Zhao X, Shin JG, et al. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002; 41(12): 913–58PubMedCrossRefGoogle Scholar
  38. 38.
    Sachse C, Brockmoller J, Bauer S, et al. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 1997 Feb; 60(2): 284–95PubMedGoogle Scholar
  39. 39.
    Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001 Apr; 27(4): 383–91PubMedCrossRefGoogle Scholar
  40. 40.
    Stewart AK, Sullivan D, Lonial S, et al. Pharmacokinetic (PK) and pharmacodynamics (PD) study of two doses of bortezomib (Btz) in patients with relapsed multiple myeloma (MM) [abstract]. Blood 2006; 108: 1008aGoogle Scholar
  41. 41.
    Dy GK, Thomas JP, Wilding G, et al. A phase I and pharmacologic trial of two schedules of the proteasome inhibitor, PS-341 (bortezomib, velcade), in patients with advanced cancer. Clin Cancer Res 2005; 11(9): 3410–6PubMedCrossRefGoogle Scholar
  42. 42.
    Blaney SM, Bernstein M, Neville K, et al. Phase I study of the proteasome inhibitor bortezomib in pediatric patients with refractory solid tumors: a Children’s Oncology Group study (ADVL0015). J Clin Oncol 2004; 22(23): 4804–9PubMedCrossRefGoogle Scholar
  43. 43.
    Hamilton AL, Eder JP, Pavlick AC, et al. Proteasome inhibition with bortezomib (PS-341): a phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle. J Clin Oncol 2005; 23(25): 6107–16PubMedCrossRefGoogle Scholar
  44. 44.
    Lara Jr PN, Koczywas M, Quinn DI, et al. Bortezomib plus docetaxel in advanced non-small cell lung cancer and other solid tumors: a phase I California Cancer Consortium trial. J Thorac Oncol 2006 Feb; 1(2): 126–34PubMedCrossRefGoogle Scholar
  45. 45.
    Aghajanian C, Dizon DS, Sabbatini P, et al. Phase I trial of bortezomib and carboplatin in recurrent ovarian or primary peritoneal cancer. J Clin Oncol 2005 Sep; 23(25): 5943–9PubMedCrossRefGoogle Scholar
  46. 46.
    Ryan DP, O’Neil BH, Supko JG, et al. A phase I study of bortezomib plus irinotecan in patients with advanced solid tumors. Cancer 2006 Dec; 107(11): 2688–97PubMedCrossRefGoogle Scholar
  47. 47.
    Ryan DP, Appleman LJ, Lynch T, et al. Phase I clinical trial of bortezomib in combination with gemcitabine in patients with advanced solid tumors. Cancer 2006 Nov; 107(10): 2482–9PubMedCrossRefGoogle Scholar
  48. 48.
    Messersmith WA, Baker SD, Lassiter L, et al. Phase I trial of bortezomib in combination with docetaxel in patients with advanced solid tumors. Clin Cancer Res 2006; 12(4): 1270–5PubMedCrossRefGoogle Scholar
  49. 49.
    Chatta GS, Rader ME, Belani CP, et al. Effect of ketoconazole administration on the pharmacokinetics (PK) and pharmacodynamics (PD) of bortezomib in patients with advanced solid tumors [abstract]. J Clin Oncol 2007; 25: 609sCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  • David I. Quinn
    • 1
  • John Nemunaitis
    • 2
  • Jyotsna Fuloria
    • 3
  • Carolyn D. Britten
    • 4
  • Nashat Gabrail
    • 5
  • Lorrin Yee
    • 6
  • Milin Acharya
    • 7
  • Kai Chan
    • 8
  • Nadine Cohen
    • 7
  • Assen Dudov
    • 9
  1. 1.University of Southern CaliforniaLos AngelesUSA
  2. 2.Mary Crowley Medical Research CenterDallasUSA
  3. 3.Oschner Cancer InstituteNew OrleansUSA
  4. 4.David Geffen School of MedicineUniversity of California Los AngelesLos AngelesUSA
  5. 5.Gabrail Cancer CenterCantonUSA
  6. 6.Northwest Medical SpecialtiesTacomaUSA
  7. 7.Johnson & Johnson, LLCRaritanUSA
  8. 8.Johnson & Johnson, LLCHigh WycombeUK
  9. 9.Sofia Cancer CentreSofiaBulgaria

Personalised recommendations