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Impact of Older Age on the Exposure of Paclitaxel: a Population Pharmacokinetic Study

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Abstract

Purpose

Limited available data suggest that older patients are more prone to develop paclitaxel-induced toxicity than their younger peers. It remains unclear whether this is related to age-dependent pharmacokinetics (PK) of paclitaxel. Primary objective of this study was to determine the influence of older age on the PK of paclitaxel.

Methods

PK data of patients aged ≥70 years who received paclitaxel intravenously at the Netherlands Cancer Institute (NKI) and the Radboud University Medical Center between September 2012 and May 2017 were collected. These prospectively collected data were pooled with previously published databases from multiple clinical trials conducted at the NKI and Erasmus MC Cancer Institute. A previously developed 3-compartment population PK model with saturable distribution and elimination was used to describe paclitaxel plasma concentration-time data. Hereafter, influence of age on paclitaxel PK was assessed in a previously established full covariate model.

Results

In total, paclitaxel PK data from 684 patients were available, consisting of 166 patients ≥70 years (24%). Median age of the cohort was 61 years (range 18 to 84 years). The impact of age, either treated as a continuous or dichotomous covariate (<70 versus ≥70 years), on the elimination of paclitaxel was only marginal but statistically significant (both p < 0.001 with no clinically relevant decrease in interindividual variability). For a typical patient, maximal elimination capacity decreased by only 5% for a 10-year increment of age.

Conclusion

In this extensive multi-center dataset, which included a considerable number of older patients, older age had no clinically relevant impact on paclitaxel PK.

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Abbreviations

A 1–3 :

Amount of paclitaxel in first-third compartment

C 1 :

log-transformed concentration of paclitaxel in central compartment

EMC:

Erasmus Medical Center Cancer Institute

HPLC-MS/MS:

High-performance liquid chromatography coupled with tandem mass spectrometry

K :

rate constant of the distribution between compartments

KM EL :

plasma concentration at half VMEL

KM TR :

plasma concentration at half VMTR

NKI:

Netherlands Cancer Institute

PK:

Pharmacokinetics

Radboud UMC:

Radboud University Medical Center

VM EL :

maximal elimination rate

VM TR :

maximal transport rate from the central to the first peripheral compartment

References

  1. NNoone A, Cronin KA, Altekruse SF, Howlader N, Lewis DR, Petkov VI, et al. Cancer incidence and survival trends by subtype using data from the Surveillance Epidemiology and End Results Program, 1992–2013. Cancer Epidemiol Biomarkers Prev. 2017;26:632–41. https://doi.org/10.1158/1055-9965.EPI-16-0520.

  2. Lewis JH, Kilgore ML, Goldman DP, Trimble EL, Kaplan R, Montello MJ, et al. Participation of patients 65 years of age or older in cancer clinical trials. J Clin Oncol. 2003;21:1383–9. https://doi.org/10.1200/JCO.2003.08.010.

    Article  PubMed  Google Scholar 

  3. Aapro MS, Köhne C-H, Cohen HJ, Extermann M. Never too old? Age should not be a barrier to enrollment in Cancer Clinical trials. Oncologist. 2005;10:189–204. https://doi.org/10.1634/theoncologist.2008-0207.

    Article  Google Scholar 

  4. Talarico L, Chen G, Pazdur R. Enrollment of elderly patients in clinical trials for cancer drug registration: A 7-year experience by the US Food and Drug Administration. J Clin Oncol. 2004;22:4626–31. https://doi.org/10.1200/JCO.2004.02.175.

    Article  PubMed  Google Scholar 

  5. Freedman RA, Dockter TJ, Lafky JM, Hurria A, Muss HJ, Cohen HJ, et al. Promoting accrual of older patients with Cancer to Clinical trials : an Alliance for Clinical trials in oncology member survey ( A171602 ). Oncologist. 2018;23:1–8. https://doi.org/10.1634/theoncologist.2018-0033.

    Article  Google Scholar 

  6. Lucas C, Byles J, Martin JH. Medicines optimisation in older people: taking age and sex into account. Maturitas. 2016;93:114–20. https://doi.org/10.1016/j.maturitas.2016.06.021.

    Article  PubMed  Google Scholar 

  7. Dawson A, Dennison E. Measuring the musculoskeletal aging phenotype. Maturitas. 2016;93:13–7. https://doi.org/10.1016/j.maturitas.2016.04.014.

  8. Seripa D, Panza F, Daragjati J, Paroni G, Pilotto A. Measuring pharmacogenetics in special groups: geriatrics. Expert Opin Drug Metab Toxicol. 2015;11:1073–88. https://doi.org/10.1517/17425255.2015.1041919.

    Article  CAS  PubMed  Google Scholar 

  9. Nakamura Y, Sekine I, Furuse K, Saijo N. Retrospective comparison of toxicity and efficacy in phase II trials of 3-h infusions of paclitaxel for patients 70 years of age or older and patients under 70 years of age. Cancer Chemother Pharmacol. 2000;46:114–8.

    Article  CAS  Google Scholar 

  10. Lichtman SM, Hollis D, A a M, Rosner GL, C a R, Lester EP, et al. Prospective evaluation of the relationship of patient age and paclitaxel clinical pharmacology: Cancer and leukemia group B (CALGB 9762). J Clin Oncol. 2006;24:1846–51. https://doi.org/10.1200/JCO.2005.03.9289.

    Article  CAS  PubMed  Google Scholar 

  11. Food and Drug Administration. TAXOL (paclitaxel). In: NDA 020262; 2011.

    Google Scholar 

  12. Joerger M, Huitema ADR, van den Bongard DHJG, Schellens JHM, Beijnen JH. Quantitative effect of gender, age, liver function, and body size on the population pharmacokinetics of paclitaxel in patients with solid tumors. Clin Cancer Res. 2006;12:2150–7. https://doi.org/10.1158/1078-0432.CCR-05-2069.

    Article  CAS  PubMed  Google Scholar 

  13. Joerger M, Kraff S, Huitema ADR, Feiss G, Moritz B, Schellens JHM, et al. Evaluation of a pharmacology-driven dosing algorithm of 3-weekly paclitaxel using therapeutic drug monitoring: A pharmacokinetic-pharmacodynamic simulation study. Clin Pharmacokinet. 2012;51:607–17. https://doi.org/10.2165/11634210-000000000-00000.

    Article  CAS  PubMed  Google Scholar 

  14. De Graan AJM, Elens L, Smid M, Martens JW, Sparreboom A, Nieuweboer AJM, et al. A pharmacogenetic predictive model for paclitaxel clearance based on the DMET platform. Clin Cancer Res. 2013;19:5210–7. https://doi.org/10.1158/1078-0432.CCR-13-0487.

    Article  CAS  PubMed  Google Scholar 

  15. Kraff S, Nieuweboer AJM, Mathijssen RHJ, Baty F, De Graan AJ, Van Schaik RHN, et al. Pharmacokinetically based dosing of weekly paclitaxel to reduce drug-related neurotoxicity based on a single sample strategy. Cancer Chemother Pharmacol. 2015;75:975–83. https://doi.org/10.1007/s00280-015-2724-9.

    Article  CAS  PubMed  Google Scholar 

  16. De Graan AJM, Elens L, Sprowl JA, Sparreboom A, Friberg LE, Van Der Holt B, et al. CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity. Clin Cancer Res. 2013;19:3316–24. https://doi.org/10.1158/1078-0432.CCR-12-3786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hendrikx JJMA, Hillebrand MJX, Thijssen B, Rosing H, Schinkel AH, Schellens JHM, et al. A sensitive combined assay for the quantification of paclitaxel, docetaxel and ritonavir in human plasma using liquid chromatography coupled with tandem mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci. 2011;879:2984–90. https://doi.org/10.1016/j.jchromb.2011.08.034.

    Article  CAS  Google Scholar 

  18. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. (ICH) 2018.

  19. Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Pharmacodyn. 2001;28:481–504. https://doi.org/10.1023/A:1012299115260.

    Article  CAS  PubMed  Google Scholar 

  20. Ma C, Bandukwala S, Burman D, Bryson J, Seccareccia D, Banerjee S, et al. Interconversion of three measures of performance status: an empirical analysis. Eur J Cancer. 2010;46:3175–83. https://doi.org/10.1016/j.ejca.2010.06.126.

    Article  PubMed  Google Scholar 

  21. Stage TB, Bergmann TK, Kroetz DL. Clinical Pharmacokinetics of paclitaxel monotherapy: an updated literature review. Clin Pharmacokinet. 2018;57:7–19. https://doi.org/10.1007/s40262-017-0563-z.

  22. Smorenburg CH, Ten Tije AJ, Verweij J, Bontenbal M, Mross K, Van Zomeren DM, et al. Altered clearance of unbound paclitaxel in elderly patients with metastatic breast cancer. Eur J Cancer. 2003;39:196–202. https://doi.org/10.1016/S0959-8049(02)00611-1.

    Article  CAS  PubMed  Google Scholar 

  23. Fidias P, Supko JG, Martins R, Boral A, Carey R, Grossbard M, et al. Measurement and impact of co-morbidity in elderly patients with advanced non-small cell lung cancer treated with chemotherapy. A phase II study of weekly paclitaxel. Clin Cancer Res. 2001;7:3942–9. https://doi.org/10.1080/02841860600833178.

    Article  CAS  PubMed  Google Scholar 

  24. Sehl M, Sawhney R, Naeim A. Physiologic aspects of aging: impact on cancer management and decision making, part II. Cancer J. 2005;11:461–73. https://doi.org/10.1097/00130404-200511000-00005.

    Article  PubMed  Google Scholar 

  25. Henningsson A, Karlsson MO, Viganò L, Gianni L, Verweij J, Sparreboom A. Mechanism-based pharmacokinetic model for paclitaxel. J Clin Oncol. 2001;19:4065–73.

    Article  CAS  Google Scholar 

  26. Mielke S, Sparreboom A, Steinberg SM, Gelderblom H, Unger C, Behringer D, et al. Association of Paclitaxel Pharmacokinetics with the development of peripheral neuropathy in patients with advanced Cancer. Clin Cancer Res. 2005;11:4843–50. https://doi.org/10.1158/1078-0432.CCR-05-0298.

    Article  CAS  PubMed  Google Scholar 

  27. Mielke S, Sparreboom A, Behringer D, Mross K. Paclitaxel pharmacokinetics and response to chemotherapy in patients with advanced cancer treated with a weekly regimen. Anticancer Res. 2005;25:4423–7.

    CAS  PubMed  Google Scholar 

  28. Gianni BL, Kearns CM, Giani A, Capri G, Vigan L, Locatelli A, et al. Nonlinear Pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/Pharmacodynamic relationships in humans. J Clin Oncol. 1995;13:180–90.

    Article  CAS  Google Scholar 

  29. Ohtsu T, Sasaki Y, Tamura T, Nishiwaki Y, Clinical Pharmacokinetics SN. Pharmacodynamics of paclitaxel: A 3-hour infusion versus a 24-hour infusion. Clin Cancer Res. 1995;1:599–606.

    CAS  PubMed  Google Scholar 

  30. Joerger M, von Pawel J, Kraff S, Fischer JR, Eberhardt W, Gauler TC, et al. Open-label, randomised study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small cell lung cancer (NSCLC). Ann Oncol. 2016;27:1895–902. https://doi.org/10.1093/annonc/mdw290.

  31. Bhalla KN, Kumar GN, Walle UK, Ibrado AM, Javed T, Stuart RK, et al. Phase I and pharmacologic study of a 3-hour infusion of paclitaxel followed by cisplatinum and 5-fluorouracil in patients with advanced solid tumors. Clin Cancer Res. 1999;5:1723–30.

    CAS  PubMed  Google Scholar 

  32. Kurata T, Tamura T, Shinkai T, Ohe Y, Kunitoh H, Kodama T, et al. Phase I and pharmacological study of paclitaxel given over 3 h with cisplatin for advanced non-small cell lung cancer. Jpn J Clin Oncol. 2001;31:93–9.

    Article  CAS  Google Scholar 

  33. De Jongh FE, De Wit R, Verweij J, Sparreboom A, Van den Bent MJ, Stoter G, et al. Dose-dense cisplatin/paclitaxel: A well-tolerated and highly effective chemotherapeutic regimen in patients with advanced ovarian cancer. Eur J Cancer. 2002;38:2005–13. https://doi.org/10.1016/S0959-8049(02)00242-3.

    Article  PubMed  Google Scholar 

  34. Belani BCP, Kearns CM, Zuhowski EG, Erkmen K, Hiponia D, Zacharski D, et al. Phase I trial , including pharmacokinetic and Pharmacodynamic correlations, of combination paclitaxel and carboplatin in patients with metastatic non–small-cell lung Cancer. J Clin Oncol. 1999;17:676–84.

    Article  CAS  Google Scholar 

  35. Huizing MT, van Warmerdam LJ, Rosing H, Schaefers MC, Lai A, Helmerhorst TJ, et al. Phase I and pharmacologic study of the combination paclitaxel and carboplatin as first-line chemotherapy in stage III and IV ovarian cancer. J Clin Oncol. 1997;15:1953–64. https://doi.org/10.1200/JCO.1997.15.5.1953.

    Article  CAS  PubMed  Google Scholar 

  36. Moreira A, Lobato R, Morais J, Silva S, Ribeiro J, Figueira A. Influence of the interval between the administration of doxorubicin and paclitaxel on the pharmacokinetics of these drugs in patients with locally advanced breast cancer. Cancer Chemother Pharmacol. 2001;48:333–7. https://doi.org/10.1007/s002800100297.

    Article  CAS  PubMed  Google Scholar 

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ACKNOWLEDGEMENTS AND DISCLOSURES

Jos H. Beijnen and Jan H.M. Schellens are (part-time) employees and shareholders of Modra Pharmaceuticals, and (partly) hold a patent on oral taxane pharmaceutical formulations. The other authors declare no conflicts of interest in connection with this manuscript. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committees and was carried out in accordance with International Conference on Harmonsation Guidelines for Good Clinical Practice. Written informed consent was obtained from all individual participants.

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Authors and Affiliations

  1. Department of Pharmacy &Pharmacology, Antoni van Leeuwenhoek – Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, the Netherlands

    Marie-Rose B. S. Crombag, Aurelia H. M. de Vries Schultink, Thomas P. C. Dorlo, Jos H. Beijnen & Alwin D. R. Huitema

  2. Division of Pharmacology, Netherlands Cancer Institute, Amsterdam, the Netherlands

    Marie-Rose B. S. Crombag, Aurelia H. M. de Vries Schultink, Jan H. M. Schellens, Thomas P. C. Dorlo, Jos H. Beijnen & Alwin D. R. Huitema

  3. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands

    Stijn L.W. Koolen, Sophie Wijngaard & Ron H. J. Mathijssen

  4. Department of Medical Oncology and Hematology, Cantonal Hospital, St Gallen, Switzerland

    Markus Joerger

  5. Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands

    Jan H. M. Schellens

  6. Department of Pharmacy and Radboud Institute of Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands

    Nielka P. van Erp

  7. Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands

    Alwin D. R. Huitema

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  1. Marie-Rose B. S. Crombag
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Correspondence to Marie-Rose B. S. Crombag.

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Crombag, MR.B.S., de Vries Schultink, A.H.M., Koolen, S.L. et al. Impact of Older Age on the Exposure of Paclitaxel: a Population Pharmacokinetic Study. Pharm Res 36, 33 (2019). https://doi.org/10.1007/s11095-018-2563-6

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