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Is age just a number? A population pharmacokinetic study of gemcitabine

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Abstract

Purpose

Pharmacokinetic exposure to gemcitabine and its metabolite, 2′,2′-difluorodeoxyuridine (dFdU), might be altered in elderly compared to their younger counterparts. It is unknown if age-based dose adjustments are necessary to reduce the development of treatment-induced adverse events. The aim of this study was to assess the impact of age on the pharmacokinetics of gemcitabine and dFdU.

Methods

Pharmacokinetic sampling following a flexible limited sampling strategy was performed in patients ≥ 70 years after gemcitabine infusion. The data were supplemented with pharmacokinetic data in patients included in four previously conducted clinical trials. Nonlinear mixed effects modelling was performed on the pooled dataset to assess the impact of age on the pharmacokinetics of gemcitabine and dFdU.

Results

In total, pharmacokinetic data were available of 197 patients, of whom 83 patients were aged ≥ 70 years (42%). A two-compartment model for both gemcitabine and dFdU with linear clearances from the central compartments described the data best. Age, tested as continuous and categorical (< 70 years versus ≥ 70 years) covariate, did not statistically affect the pharmacokinetics of gemcitabine and dFdU.

Conclusion

Age was not of influence on the pharmacokinetics of gemcitabine or its metabolite, dFdU. Age-related dose adjustments for gemcitabine based on pharmacokinetic considerations are not recommended.

Trial registration number

ntr-3964704812, registered on May 3rd 2012.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Author information

Authors and Affiliations

  1. Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute-Antoni Van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    René J. Boosman, Jos H. Beijnen & Alwin D. R. Huitema

  2. Department of Hospital Pharmacy, Erasmus MC, Rotterdam, The Netherlands

    Marie-Rose B. S. Crombag

  3. Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands

    Nielka P. van Erp

  4. Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

    Jos H. Beijnen

  5. Department of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute-Antoni Van Leeuwenhoek, Amsterdam, The Netherlands

    Neeltje Steeghs

  6. Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

    Alwin D. R. Huitema

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

    Alwin D. R. Huitema

Authors
  1. René J. Boosman
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  2. Marie-Rose B. S. Crombag
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Corresponding author

Correspondence to René J. Boosman.

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Conflict of interest

R.J. Boosman, M.B.S. Crombag and A.D.R. Huitema declare that they have no conflict of interest. N.P. van Erp received research grant from Astellas, Janssen-Cilag and Ipsen. J.H. Beijnen has received payment for expert testimony for Hoyng Tokh Monegier (paid to their institution), is a part-time employee and (in)direct stockholder of Modra Pharmaceuticals and (jointly) holds a patent on oral taxane formulations, which are clinically developed by Modra Pharmaceuticals. Modra Pharmaceuticals is a small spin-off company of the Netherlands Cancer Institute. All of these conflicts are outside of the submitted work. N. Steeghs provided consultation or attended advisory boards for Boehringer Ingelheim, Ellipses Pharma. N Steeghs received research grants for the institute from AB Science, Abbvie, Actuate Therapeutics, ADCtherapeutics, Amgen, Array, Ascendis Pharma, Astex, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BridgeBio, Bristol-Myers Squibb, Cantargia, Celgene, CellCentric, Cresecendo, Cytovation, Deciphera, Eli Lilly, Exelixis, Genentech, Genmab, Gilead, GlaxoSmithKline, Incyte, InteRNA, Janssen/Johnson&Johnson, Kinate, Merck, Merck Sharp & Dohme, Merus, Molecular Partners, Novartis, Numab, Pfizer, Pierre Fabre, Regeneron, Roche, Sanofi, Seattle Genetics, Servier, Taiho, Takeda (outside the submitted work).

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Boosman, R.J., Crombag, MR.B.S., van Erp, N.P. et al. Is age just a number? A population pharmacokinetic study of gemcitabine. Cancer Chemother Pharmacol 89, 697–705 (2022). https://doi.org/10.1007/s00280-022-04431-5

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  • DOI: https://doi.org/10.1007/s00280-022-04431-5

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