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Does Older Age Lead to Higher Risk for Neutropenia in Patients Treated with Paclitaxel?

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Abstract

Purpose

There is ongoing concern regarding increased toxicity from paclitaxel in elderly patients, particularly of severe neutropenia. Yet, data so far is controversial and this concern is not supported by a clinically relevant age-dependent difference in pharmacokinetics (PK) of paclitaxel. This study assessed whether age is associated with increased risk for paclitaxel-induced neutropenia.

Methods

Paclitaxel plasma concentration-time data, pooled from multiple different studies, was combined with available respective neutrophil count data during the first treatment cycle. Paclitaxel pharmacokinetic-pharmacodynamic (PK-PD) data was modeled using a non-linear mixed effects approach and a semiphysiological neutropenia model, where systemic paclitaxel exposure was linked to reduced proliferation of neutrophils. The impact of age was evaluated on relevant variables in the model, using a significance threshold of p < 0.005.

Results

Paclitaxel PK-PD data was evaluated from 300 patients, with a median age of 65 years (range 23–84 years), containing 116 patients ≥70 years (39%). First cycle neutrophil counts were adequately described by a threshold effect model of paclitaxel on the proliferation rate of neutrophils. Age as a continuous or dichotomous variable (≥70 versus <70 years) did not significantly impact sensitivity of the bone marrow to paclitaxel nor the average maturation time of neutrophils (both p > 0.005), causing a decline in the respective interindividual variability of <1%.

Conclusion

Results from this large retrospective patient cohort do not suggest elderly patients to be at an increased risk of developing paclitaxel-associated neutropenia during the first treatment cycle. Reflexive dose reductions of paclitaxel in elderly patients are unlikely to improve the risk of severe neutropenia and may be deleterious.

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Abbreviations

ANCbase :

Baseline absolute neutrophil count

ANCt :

Absolute neutrophil count at time t

Cdrug :

Systemic drug concentration

EC50 :

Drug concentration at half the maximum inhibitory effect

E drug :

Drug effect

Emax :

Maximum inhibiting drug effect

Erasmus MC:

Erasmus Medical Center Cancer Institute

FB:

Feedback

IIV:

Interindividual variability

k prol :

Rate constant for the proliferation of neutrophils

k tr :

Rate constant for the maturation of neutrophils

MTT:

Mean transit time

NKI:

Netherlands Cancer Institute

PK-PD:

Pharmacokinetic-pharmacodynamic

Radboud UMC :

Radboud University Medical Center

SLOPE:

Slope factor of linear drug effect

Tc > 0.05μM :

Time-above-threshold concentration of 0.05 μmol/L

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors wish to express their gratitude to all study participants and health care employees involved in patient inclusion, with special thanks to Ellen van der Pan and Anoek van Straten. The authors thank the Research High Performance Computing facility of the NKI for support in the use of computational resources. Jos H. Beijnen is a (part-time) employee and 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. 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.

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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, 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, 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 Hospital Pharmacy, Erasmus MC, Rotterdam, the Netherlands

    Stijn L. W. Koolen

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

    Markus Joerger

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

    Nielka P. van Erp

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

    Jos H. Beijnen

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

    Alwin D. R. Huitema

Authors
  1. Marie-Rose B. S. Crombag
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  2. Stijn L. W. Koolen
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  9. Alwin D. R. Huitema
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Correspondence to Marie-Rose B. S. Crombag.

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Crombag, MR.B.S., Koolen, S.L.W., Wijngaard, S. et al. Does Older Age Lead to Higher Risk for Neutropenia in Patients Treated with Paclitaxel?. Pharm Res 36, 163 (2019). https://doi.org/10.1007/s11095-019-2697-1

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  • DOI: https://doi.org/10.1007/s11095-019-2697-1

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