Impact of Older Age on the Exposure of Paclitaxel: a Population Pharmacokinetic Study
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.
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.
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.
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 wordsage differences older patients paclitaxel pharmacokinetics
Amount of paclitaxel in first-third compartment
log-transformed concentration of paclitaxel in central compartment
Erasmus Medical Center Cancer Institute
High-performance liquid chromatography coupled with tandem mass spectrometry
rate constant of the distribution between compartments
plasma concentration at half VMEL
plasma concentration at half VMTR
Netherlands Cancer Institute
- Radboud UMC
Radboud University Medical Center
maximal elimination rate
maximal transport rate from the central to the first peripheral compartment
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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