Advertisement

Pharmaceutical Research

, 36:181 | Cite as

Exposure to Docetaxel in the Elderly Patient Population: a Population Pharmacokinetic Study

  • Marie-Rose B. S. CrombagEmail author
  • Thomas P. C. Dorlo
  • Ellen van der Pan
  • Anoek van Straten
  • Andries M. Bergman
  • Nielka P. van Erp
  • Jos H. Beijnen
  • Alwin D. R. Huitema
Research Paper
  • 87 Downloads

Abstract

Background

Docetaxel is commonly used in elderly patients, who are frequently diagnosed with prostate cancer. Although previous studies revealed no clinically relevant impact of older age on docetaxel pharmacokinetics (PK), this may be masked by indication. Metastatic castration-resistant prostate cancer (mCRPC) patients were reported to have approximately two-times lower systemic exposure compared to patients with other solid tumors. This study assessed the impact of older age on docetaxel PK, also considering the effect of indication on docetaxel PK.

Methods

Prospectively collected docetaxel PK data from patients aged ≥70 was pooled with PK data from an earlier published multicenter study. A 3-compartment population PK model, including multiple covariates, was used to describe docetaxel plasma concentration-time data. We added the effect of prostate cancer (mCRPC and metastatic hormone-sensitive prostate cancer (mHSPC)) on clearance to this model. Hereafter, we evaluated the additional impact of older age on docetaxel clearance, using a significance threshold of p < 0.005.

Results

Docetaxel plasma concentration-time data from 157 patients were analyzed. Median age in the total cohort was 67 years (range 31-87), with 49% of the total cohort aged ≥70. The impact of age on docetaxel clearance was statistically significant (p < 0.005). For a typical patient, a 10-year and 20-year increase of age led to a reduction in clearance of 17% and 34%, respectively.

Conclusion

In this cohort study, age significantly and independently affected docetaxel clearance, showing lower docetaxel clearance in elderly patients. In our cohort, mCRPC and mHSPC patients both had higher clearance than patients with other solid tumors.

KEY WORDS

pharmacokinetics docetaxel older age prostate cancer 

Notes

ACKNOWLEDGMENTS AND DISCLOSURES

No sources of funding were used in the preparation of this manuscript. Jos H. Beijnen is (part-time) employee and (indirect) shareholder of Modra Pharmaceuticals and (partly) holds a patent on oral taxane pharmaceutical formulations. The other authors declare no conflicts of interest in connection with this manuscript.

The authors wish to express their gratitude to all study participants and engaged medical workers (physicians and nurses) who made this work possible. The authors thank the Research High Performance Computing facility of the NKI for support in the use of computational resources. 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 ICH Guidelines for Good Clinical Practice. Written informed consent was obtained from all individual participants.

References

  1. 1.
    DRUGDEX®. Truven health analytics. Docetaxel. 2015.Google Scholar
  2. 2.
    Food and Drug Administration. Official label - taxotere (docetaxel), NDA 020449. 2015.Google Scholar
  3. 3.
    Bruno R, Vivier N, Vergniol JC, De Phillips SL, Montay G, Sheiner LB. A population pharmacokinetic model for docetaxel (Taxotere): model building and validation. J Pharmacokinet Biopharm. 1996;24:153–72.CrossRefGoogle Scholar
  4. 4.
    Bruno R, Vivier N, Veyrat-Follet C, Montay G, Rhodes GR. Population pharmacokinetics and pharmacokinetic-pharmacodynamic relationships for docetaxel. Investig New Drugs. 2001;19:163–9.CrossRefGoogle Scholar
  5. 5.
    Bosch TM, Huitema ADR, Doodeman VD, Jansen R, Witteveen E, Smit WM, et al. Pharmacogenetic screening of CYP3A and ABCB1 in relation to population pharmacokinetics of docetaxel. Clin Cancer Res. 2006;12:5786–93.CrossRefGoogle Scholar
  6. 6.
    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.CrossRefGoogle Scholar
  7. 7.
    Crombag MRBS, Joerger M, Thürlimann B, Schellens JHM, Beijnen JH, Huitema ADR. Pharmacokinetics of selected anticancer drugs in elderly cancer patients: focus on breast cancer. Cancers (Basel). 2016;8.Google Scholar
  8. 8.
    de Vries Schultink A, Crombag M, van Werkhoven E, Otten H, Bergman A, Schellens J, et al. Neutropenia and docetaxel exposure in metastatic castration-resistant prostate cancer patients: a meta-analysis and evaluation of a clinical cohort. Cancer Med. 2019;8:1406–15.CrossRefGoogle Scholar
  9. 9.
    Franke RM, Carducci MA, Rudek MA, Baker SD, Sparreboom A. Castration-dependent pharmacokinetics of docetaxel in patients with prostate cancer. J Clin Oncol. 2010;28:4562–7.CrossRefGoogle Scholar
  10. 10.
    Belderbos BPS, Hussaarts KGAM, van Harten LJ, Oomen-de Hoop E, de Bruijn P, Hamberg P, et al. Effects of prednisone on docetaxel pharmacokinetics in men with metastatic prostate cancer: a randomized drug-drug interaction study. Br J Clin Pharmacol. 2019; 986–92.CrossRefGoogle Scholar
  11. 11.
    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.CrossRefGoogle Scholar
  12. 12.
    The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. (ICH). 2018. www.ich.org.
  13. 13.
    Cornford P, Bellmunt J, Bolla M, Briers E, De Santis M, Gross T, et al. EAU-ESTRO-SIOG guidelines on prostate cancer. Part II: treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol. 2017;71:630–42.CrossRefGoogle Scholar
  14. 14.
    Vale CL, Burdett S, Rydzewska LHM, Albiges L, Clarke NW, Fisher D, et al. Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data. Lancet Oncol. 2016;17:243–56.CrossRefGoogle Scholar
  15. 15.
    Dosne AG, Bergstrand M, Harling K, Karlsson MO. Improving the estimation of parameter uncertainty distributions in nonlinear mixed effects models using sampling importance resampling. J Pharmacokinet Pharmacodyn. 2016;43:583–96.CrossRefGoogle Scholar
  16. 16.
    Hutson PR, Oettel K, Douglas J, Ritter M, Messing E, Staab MJ, et al. Effect of medical castration on CYP3A4 enzyme activity using the erythromycin breath test. Cancer Chemother Pharmacol. 2008;62:373–7.CrossRefGoogle Scholar
  17. 17.
    Minami H, Ohe Y, Niho S, Goto K, Ohmatsu H, Kubota K, et al. Comparison of pharmacokinetics and pharmacodynamics of docetaxel and cisplatin in elderly and non-elderly patients: why is toxicity increased in elderly patients? J Clin Oncol. 2004;22:2901–8.CrossRefGoogle Scholar
  18. 18.
    Slaviero KA, Clarke SJ, McLachlan AJ, Blair EYL, Rivory LP. Population pharmacokinetics of weekly docetaxel in patients with advanced cancer. Br J Clin Pharmacol. 2004;57:44–53.CrossRefGoogle Scholar
  19. 19.
    ten Tije AJ, Verweij J, Carducci MA, Graveland W, Rogers T, Pronk T, et al. Prospective evaluation of the pharmacokinetics and toxicity profile of docetaxel in the elderly. J Clin Oncol. 2005;23:1070–7.CrossRefGoogle Scholar
  20. 20.
    Hurria A, Fleming MT, Baker SD, Kelly WK, Cutchall K, Panageas K, et al. Pharmacokinetics and toxicity of weekly docetaxel in older patients. Clin Cancer Res. 2006;12:6100–5.CrossRefGoogle Scholar
  21. 21.
    Yamamoto N, Tamura T, Kamiya Y, Sekine I, Kunitoh H, Saijo N. Correlation between docetaxel clearance and estimated cytochrome P450 activity by urinary metabolite of exogenous cortisol. J Clin Oncol. 2000;18:2301–8.CrossRefGoogle Scholar
  22. 22.
    Michael M, Cullinane C, Hatzimihalis A, O’Kane C, Milner A, Booth R, et al. Docetaxel pharmacokinetics and its correlation with two in vivo probes for cytochrome P450 enzymes: the C 14-erythromycin breath test and the antipyrine clearance test. Cancer Chemother Pharmacol. 2012;69:125–35.CrossRefGoogle Scholar
  23. 23.
    James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387:1163–77.  https://doi.org/10.1016/S0140-6736(15)01037-5.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Gravis G, Audenet F, Irani J, Timsit MO, Barthelemy P, Beuzeboc P, et al. Chemotherapy in hormone-sensitive metastatic prostate cancer: evidences and uncertainties from the literature. Cancer Treat Rev. 2017;55:211–7.CrossRefGoogle Scholar
  25. 25.
    Hooker A, ten Tije A, Carducci M, Weber J, Garrett-Mayer E, Gelderblom H, et al. Population pharmacokinetic model for docetaxel in patients with varying degrees of liver function: incorporating cytochrome P450 3A activity measurements. Clin Parmacol Ther. 2008;84:111–8.CrossRefGoogle Scholar
  26. 26.
    Klotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev. 2009;41:67–76.CrossRefGoogle Scholar
  27. 27.
    Fukae M, Shiraishi Y, Hirota T, Sasaki Y, Yamahashi M, Takayama K, et al. Population pharmacokinetic-pharmacodynamic modeling and model-based prediction of docetaxel-induced neutropenia in Japanese patients with non-small cell lung cancer. Cancer Chemother Pharmacol. 2016;78:1013–23.CrossRefGoogle Scholar
  28. 28.
    Rosing H, Lustig V, Van Warmerdam LJC, Huizing MT, Ten Bokkel Huinink WW, Schellens JHM, et al. Pharmacokinetics and metabolism of docetaxel administered as a 1-h intravenous infusion. Cancer Chemother Pharmacol. 2000;45:213–8.CrossRefGoogle Scholar
  29. 29.
    John V, Mashru S, Lichtman S. Pharmacological factors influencing anticancer drug selection in the elderly. Drugs Aging. 2003;20:737–59.CrossRefGoogle Scholar
  30. 30.
    European Medicines Agency. Summary of product characteristics - taxotere (docetaxel). 2015.Google Scholar
  31. 31.
    Trump DL. Commentary on “Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): A randomised, open-label, phase 3 trial”. Urol Oncol. 2013;31:1845.Google Scholar
  32. 32.
    Droz JP, Albrand G, Gillessen S, Hughes S, Mottet N, Oudard S, et al. Management of prostate cancer in elderly patients: recommendations of a task force of the International Society of Geriatric Oncology. Eur Urol. 2017;72:521–31.CrossRefGoogle Scholar
  33. 33.
    Choi JH, Choi J, Chung SM, Oh JY, Lee YS, Min KH, et al. The clinical efficacy and safety of four-weekly docetaxel as first-line therapy in elderly lung Cancer patients with squamous cell carcinoma. Tuberc Respir Dis (Seoul). 2018;81:1–6.CrossRefGoogle Scholar
  34. 34.
    Maia MC, Pereira AAL, Lage LV, Fraile NM, Vaisberg V Van, Kudo G, et al. Efficacy and safety of docetaxel in elderly patients with metastatic castration-resistant prostate cancer. J Glob Oncol. 2017; 1–9.Google Scholar
  35. 35.
    Crombag MRBS, de Vries Schultink AHM, Van Doremalen JGC, Martin H, Andries O, Jan MB, et al. Age - associated hematological toxicity in patients with metastatic castration - resistant prostate cancer treated with docetaxel in clinical practice. Drugs Aging. 2019;36:379–85.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacy & PharmacologyAntoni van Leeuwenhoek – Netherlands Cancer InstituteAmsterdamthe Netherlands
  2. 2.Division of PharmacologyNetherlands Cancer InstituteAmsterdamthe Netherlands
  3. 3.Division of Medical OncologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  4. 4.Department of Pharmacy and Radboud Institute of Health SciencesRadboud University Medical CenterNijmegenthe Netherlands
  5. 5.Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical PharmacologyUtrecht UniversityUtrechtthe Netherlands
  6. 6.Department of Clinical Pharmacy, University Medical Center UtrechtUtrecht UniversityUtrechtthe Netherlands

Personalised recommendations