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Pharmaceutical Research

, 36:33 | Cite as

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

  • Marie-Rose B. S. CrombagEmail author
  • Aurelia H. M. de Vries Schultink
  • Stijn L.W. Koolen
  • Sophie Wijngaard
  • Markus Joerger
  • Jan H. M. Schellens
  • Thomas P. C. Dorlo
  • Nielka P. van Erp
  • Ron H. J. Mathijssen
  • Jos H. Beijnen
  • Alwin D. R. Huitema
Research Paper

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.

Key words

age differences older patients paclitaxel pharmacokinetics 

Abbreviations

A1–3

Amount of paclitaxel in first-third compartment

C1

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

KMEL

plasma concentration at half VMEL

KMTR

plasma concentration at half VMTR

NKI

Netherlands Cancer Institute

PK

Pharmacokinetics

Radboud UMC

Radboud University Medical Center

VMEL

maximal elimination rate

VMTR

maximal transport rate from the central to the first peripheral compartment

Notes

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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Copyright information

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

Authors and Affiliations

  • Marie-Rose B. S. Crombag
    • 1
    • 2
    Email author
  • Aurelia H. M. de Vries Schultink
    • 1
    • 2
  • Stijn L.W. Koolen
    • 3
  • Sophie Wijngaard
    • 3
  • Markus Joerger
    • 4
  • Jan H. M. Schellens
    • 2
    • 5
  • Thomas P. C. Dorlo
    • 1
    • 2
  • Nielka P. van Erp
    • 6
  • Ron H. J. Mathijssen
    • 3
  • Jos H. Beijnen
    • 1
    • 2
  • Alwin D. R. Huitema
    • 1
    • 2
    • 7
  1. 1.Department of Pharmacy &PharmacologyAntoni van Leeuwenhoek – Netherlands Cancer InstituteAmsterdamthe Netherlands
  2. 2.Division of PharmacologyNetherlands Cancer InstituteAmsterdamthe Netherlands
  3. 3.Department of Medical OncologyErasmus MC Cancer InstituteRotterdamthe Netherlands
  4. 4.Department of Medical Oncology and HematologyCantonal HospitalSt GallenSwitzerland
  5. 5.Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical PharmacologyUtrecht UniversityUtrechtthe Netherlands
  6. 6.Department of Pharmacy and Radboud Institute of Health SciencesRadboud University Medical CenterNijmegenthe Netherlands
  7. 7.Department of Clinical PharmacyUniversity Medical Center Utrecht, Utrecht UniversityUtrechtthe Netherlands

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