Advertisement

Cyclophosphamide dose adjustment based on body weight and albuminemia in elderly patients treated with R-mini-CHOP

  • E. Baudry
  • S. Huguet
  • A. L. Couderc
  • P. Chaibi
  • F. Bret
  • C. Verny
  • S. Weill
  • O. Madar
  • S. Urien
  • Keyvan RezaiEmail author
Original Article
  • 58 Downloads

Abstract

Background

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in elderly patients, and R-CHOP chemotherapy is the standard treatment protocol for DLBCL. Elderly patients (often defined as 75 years of age) are treated with anticancer drugs with precaution; however, the pharmacokinetics and pharmacodynamics (PK and PD) of these agents have not been thoroughly investigated in this population. In this study, we investigated the PK of cyclophosphamide (CP) and doxorubicin (DOXO) in elderly patients in order to verify if there is an influence of age on the PK of these anticancer drugs.

Materials and methods

This is a prospective multi-center clinical trial investigating the PK of CP and DOXO in elderly and very elderly patients with DLBCL treated by R-mini-CHOP regimen. Dose levels were 25 mg/m2, 0.7–1.4 mg/m2, 750 mg/m2, and 375 mg/m2 for DOXO, Vincristine (VCR), CP, and Rituximab, respectively. For PK analysis, 7 time point samples were collected over 48 h post-administration on cycle 3. CP and VCR plasma concentrations were measured using UPLC–MS/MS validated method. DOX plasma concentrations were measured using UPLC coupled with fluorescence detection-validated method. PK-POP modeling has been performed with a non-linear mixed-effect model program (Monolix).

Results

31 patients (15 males and 16 females), 75 to 96 years old, were treated with R-miniCHOP protocol. Among them, 19 patients were treated with VCR. A one-compartment (1cpt) open model with linear elimination adequately described CP concentration–time courses. The population PK parameters for CP were: CL = 3.58 L/h, Vmale = 32.2 L, and Vfemale = 28.7 L. Body weight (BW), albuminemia, and gender demonstrated a significant impact on CP PK. A 2-compartment (2cpt) open model with linear elimination best described DOXO concentration–time courses. The population PK parameters for DOXO obtained for the structural model were: CL = 51.1 L/h, Q = 49.6 L/h, V1 = 29.4 L, V2 = 1,130 L (clearances: CL, Q, volumes of distribution: V1, V2). The main covariate effects on DOXO PK were related to gender, BW, and VCR administration. VCR increases DOXO V1 from 29.4 L to 57.5 L (p = 0.02). No hematologic and cardiac grade 3 or 4 toxicity were recorded.

Conclusions

Usually, in the absence of specific data, the majority of the physicians empirically reduce anticancer drug dose in the elderly patients (Tourani in J Geriatr Oncol 3(1): 41–48, 2012), or even does not treat these very-old patients. A better knowledge of the pharmacokinetics in very-old patients should allow a better dose adjustment based on the most significant physiological factors that modify the pharmacokinetic parameters. In this study, no serious toxicity was observed in these very elderly patients (84.1 years). This indicates that dose adjustment of chemotherapies should not only be based on age and creatinine clearance, but also, based upon appropriate physiological and biological data. Our findings indicate that, CP dose adjustment should be done according to serum albumin levels and patients BW and gender.

Keywords

Eldelrly patients R-mini-CHOP Pharmacokinetics Dose adjustment 

Notes

Author contributions

Concept and design: EB, PC, KR. Data collection: EB, AL. Couderc, analysis and interpretation of data: SH, FB, SW, OM, KR. Manuscript writing and approval: EB, CV, SU, KR.

Compliance with ethical standards

Conflict of interest

None of the authors has conflicts of interest directly related to the contents of this review.

References

  1. 1.
    World Health Organization, National Institute on Aging, National Institutes of Health, U.S. Department of Health and Human Services (2011) Global health and aging. https://www.nia.nih.gov/research/publication/global-health-and-aging/overview. Accessed 12 Feb 2017
  2. 2.
    United Nations, Department of Economic and Social Affairs, Population Division. World population prospects, the 2017 revision. https://esa.un.org/unpd/wpp/. Accessed 12 Feb 2017
  3. 3.
    Soto-Perez-de-Celis E, de Glas NA, Hsu T, Kanesvaran R, Steer C, Navarrete-Reyes AP, Battisti NML, Chavarri-Guerra Y, O’Donovan A, Avila-Funes JA, Hurria A (2017) Global geriatric oncology: achievements and challenges. J Geriatr Oncol.  https://doi.org/10.1016/j.jgo.2017.06.001 ([Epub ahead of print] Review. PubMed PMID: 28642040)Google Scholar
  4. 4.
    The World Bank (2018) World Development Indicators. Life expectancy at birth, total (years). http://data.worldbank.org/indicator/SP.DYN.LE00.IN. Accessed 23 Sept 2016
  5. 5.
    Balducci L, Extermann M (2000) Cancer and aging. An evolving panorama. Hematol Oncol Clin N Am 14(1):1–16 (Review. PubMed PMID: 10680068)CrossRefGoogle Scholar
  6. 6.
    Balducci L, Extermann M (1997) Cancer chemotherapy in the older patient: what the medical oncologist needs to know. Cancer 80(7):1317–1322 (Review. PubMed PMID: 9317185)CrossRefGoogle Scholar
  7. 7.
    Tranchand B, Falandry C, You B, Girard P, Ribba B, Tod M, Freyer G (2008) Pharmacology of anticancer drugs in the elderly: tools for dose-adjustment. Bull Cancer 95:F21–F27.  https://doi.org/10.1684/bdc.2007.0541 (French. PubMed PMID: 18511363)Google Scholar
  8. 8.
    Kasel D, Jetter A, Harlfinger S, Gebhardt W, Fuhr U (2004) Quantification of cyclophosphamide and its metabolites in urine using liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 18(13):1472–1478 (PubMed PMID: 15216508)CrossRefGoogle Scholar
  9. 9.
    Gilbert CM, McGeary RP, Filippich LJ, Norris RL, Charles BG (2005) Simultaneous liquid chromatographic determination of doxorubicin and its major metabolite doxorubicinol in parrot plasma. J Chromatogr B Anal Technol Biomed Life Sci 826(1–2):273–276 (Epub 2005 Sep 15. PubMed PMID: 16168722)CrossRefGoogle Scholar
  10. 10.
    De Baerdemaeker LE, Mortier EP, Struys MM (2004) PK in obese patients. Contin Educ Anaesth Crit Care Pain 4:152–155CrossRefGoogle Scholar
  11. 11.
    Crombag MR, Joerger M, Thürlimann B, Schellens JH, Beijnen JH, Huitema AD (2016) PK of selected anticancer drugs in elderly cancer patients: focus on breast cancer. Cancers (Basel).  https://doi.org/10.3390/cancers8010006 (PubMed PMID: 26729170; PubMed Central PMCID: PMC4728453)Google Scholar
  12. 12.
    Zulman DM, Sussman JB, Chen X, Cigolle CT, Blaum CS, Hayward RA (2011) Examining the evidence: a systematic review of the inclusion and analysis of older adults in randomized controlled trials. J Gen Intern Med 26(7):783–790.  https://doi.org/10.1007/s11606-010-1629-x (Epub 2011 Feb 1. Review. PubMed PMID: 21286840; PubMed Central PMCID: PMC3138606)CrossRefGoogle Scholar
  13. 13.
    Wilde S, Jetter A, Rietbrock S, Kasel D, Engert A, Josting A, Klimm B, Hempel G, Reif S, Jaehde U, Merkel U, Busse D, Schwab M, Diehl V, Fuhr U (2007) Population PK of the BEACOPP polychemotherapy regimen in Hodgkin’s lymphoma and its effect on myelotoxicity. Clin Pharmacokinet 46(4):319–333 (PubMed PMID: 17375983)CrossRefGoogle Scholar
  14. 14.
    Joerger M, Huitema AD, Richel DJ, Dittrich C, Pavlidis N, Briasoulis E, Vermorken JB, Strocchi E, Martoni A, Sorio R, Sleeboom HP, Izquierdo MA, Jodrell DI, Féty R, de Bruijn E, Hempel G, Karlsson M, Tranchand B, Schrijvers AH, Twelves C, Beijnen JH, Schellens JH (2007) EORTC-PAMM-NDDG. Population PK and PD of doxorubicin and cyclophosphamide in breast cancer patients: a study by the EORTC-PAMM-NDDG. Clin Pharmacokinet 46(12):1051–1068 (PubMed PMID: 18027989)CrossRefGoogle Scholar
  15. 15.
    Piscitelli SC, Rodvold KA, Rushing DA, Tewksbury DA (1993) PK and PD of doxorubicin in patients with small cell lung cancer. Clin Pharmacol Ther 53(5):555–561 (PubMed PMID: 8387903)CrossRefGoogle Scholar
  16. 16.
    Sweatman TW, Lokich JJ, Israel M (1989) Clinical pharmacology of continuous infusion doxorubicin. Ther Drug Monit 11(1):3–9 (PubMed PMID: 2911850)CrossRefGoogle Scholar
  17. 17.
    Rudek MA, Sparreboom A, Garrett-Mayer ES, Armstrong DK, Wolff AC, Verweij J, Baker SD (2004) Factors affecting pharmacokinetic variability following doxorubicin and docetaxel-based therapy. Eur J Cancer 40(8):1170–1178 (PubMed PMID: 15110880)CrossRefGoogle Scholar
  18. 18.
    Dobbs NA, Twelves CJ, Gillies H, James CA, Harper PG, Rubens RD (1995) Gender affects doxorubicin PK in patients with normal liver biochemistry. Cancer Chemother Pharmacol 36(6):473–476 (PubMed PMID: 7554038)CrossRefGoogle Scholar
  19. 19.
    Wong AL, Seng KY, Ong EM, Wang LZ, Oscar H, Cordero MT, Copones R, Fan L, Tan SH, Goh BC, Lee SC (2014) Body fat composition impacts the hematologic toxicities and PK of doxorubicin in Asian breast cancer patients. Breast Cancer Res Treat 144(1):143–152.  https://doi.org/10.1007/s10549-014-2843-8 (Epub 2014 Jan 31. PubMed PMID: 24481679)CrossRefGoogle Scholar
  20. 20.
    Li J, Gwilt PR (2003) The effect of age on the early disposition of doxorubicin. Cancer Chemother Pharmacol 51(5):395–402 (Epub 2003 Apr 1. PubMed PMID: 12679882)Google Scholar
  21. 21.
    Safa AR, Roberts S, Agresti M, Fine RL (1994) Tamoxifen aziridine, a novel affinity probe for P-glycoprotein in multidrug resistant cells. Biochem Biophys Res Commun 202(1):606–612 (PubMed PMID: 7913604)CrossRefGoogle Scholar
  22. 22.
    Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM (1999) Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 39:361–398 (Review. PubMed PMID: 10331089)CrossRefGoogle Scholar
  23. 23.
    Tourani JM, Mourey L, Servent V, Nguyen T, Ravaud A, Girre V, Favrel S, Pinel MC, Isambert N (2012) Influence of age on the PK of i.v. vinflunine: results of a phase I trial in elderly cancer patients. J Geriatr Oncol 3(1):41–48 (ISSN 1879-4068)CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Unité de Geriatrie Aigüe CHU BicêtreLe Kremlin-BicêtreFrance
  2. 2.Radio-Pharmacology DepartmentInstitut CurieSaint CloudFrance
  3. 3.Service de Médecine InterneGériatrie et Thérapeutique-Assistance publique des hopitaux de MarseilleMarseilleFrance
  4. 4.Hôpitaux universitaires La Pitié-Salpêtrière-Charles-FoixIvry-sur-SeineFrance
  5. 5.INSERMParisFrance

Personalised recommendations