Clinical validation study of dried blood spot for determining everolimus concentration in patients with cancer

A. E. C. A. B. Willemsen*, L. M. Knapen, Y. M. de Beer, R. J. M. Bruggemann, S. Croes, C. M. L. van Herpen, N. P. van Erp

*Corresponding author for this work

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Abstract

Everolimus treatment is seriously hampered by its toxicity profile. As a relationship between everolimus exposure and effectiveness and toxicity has been established, early and ongoing concentration measurement can be key to individualize the dose and optimize treatment outcomes. Dried blood spot (DBS) facilitates sampling at a patients' home and thereby eases dose individualization. The aim of this study is to determine the agreement and predictive performance of DBS compared to whole blood (WB) to measure everolimus concentrations in cancer patients. Paired DBS and WB samples were collected in 22 cancer patients treated with everolimus and analyzed using UPLC-MS/MS. Bland-Altman and Passing-Bablok analysis were used to determine method agreement. Limits of clinical relevance were set at a difference of +/- 25%, as this would lead to a different dosing advice. Using DBS concentration and Passing-Bablok regression analysis, WB concentrations were predicted. Samples of 20 patients were suitable for analysis. Bland-Altman analysis showed a mean ratio of everolimus WB to DBS concentrations of 0.90, with 95% of data points within limits of clinical relevance. Passing-Bablok regression of DBS compared to WB revealed no constant bias (intercept 0.02; 95% CI 0.93-1.35) and a small proportional bias (slope 0.89; 95% CI 0.76-0.99). Predicted concentrations showed low bias and imprecision and 90% of samples had an absolute percentage prediction error of < 20%. DBS is a valid method to determine everolimus concentrations in cancer patients. This can especially be of value for early recognition of over- or underexposure to enable dose adaptations.
Original languageEnglish
Pages (from-to)465-471
Number of pages7
JournalEuropean Journal of Clinical Pharmacology
Volume74
Issue number4
DOIs
Publication statusPublished - 1 Apr 2018

Keywords

  • Cancer
  • Everolimus
  • Dried blood spot
  • Pharmacokinetics
  • Therapeutic drug monitoring
  • Method agreement
  • TANDEM MASS-SPECTROMETRY
  • RENAL-CELL CARCINOMA
  • NEUROENDOCRINE TUMORS
  • CYCLOSPORINE-A
  • PHASE-I
  • HEMATOCRIT
  • PHARMACOKINETICS
  • PERFORMANCE
  • TACROLIMUS
  • EXPOSURE
  • Predictive Value of Tests
  • Antineoplastic Agents/administration & dosage
  • Dried Blood Spot Testing
  • Humans
  • Middle Aged
  • Male
  • Tandem Mass Spectrometry
  • Drug Dosage Calculations
  • Chromatography, Liquid
  • Adult
  • Female
  • Reproducibility of Results
  • Drug Monitoring/methods
  • Aged
  • Everolimus/administration & dosage
  • Neoplasms/blood

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