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Evaluation of 5-Fluorouracil Pharmacokinetics in Cancer Patients with a C.1905+1G>A Mutation in DPYD by Means of a Bayesian Limited Sampling Strategy

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Abstract

Background and Objective

Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme in the catabolism of 5-fluorouracil (5FU) and DPD deficiency is an important pharmacogenetic syndrome. So far, only very limited information is available regarding the pharmacokinetics of 5FU in patients with a (partial) DPD deficiency and no limited sampling models have been developed taking into account the non-linear pharmacokinetic behaviour of 5FU. The aim of this study was to evaluate the pharmacokinetics of 5FU and to develop a limited sampling strategy to detect decreased 5FU elimination in patients with a c.1905+1G>A-related DPD deficiency.

Methods

Thirty patients, heterozygous for the C.1905+1G>A mutation in DPYD, and 18 control patients received a dose of 5FU 300 mg/m2 and/or 5FU 450 mg/m2, followed by pharmacokinetic analysis of the 5FU plasma levels. A population pharmacokinetic analysis was performed in order to develop a compartmental pharmacokinetic model suitable for a limited sampling strategy. Clinical aspects of treating DPD-deficient patients with 5FU-based chemotherapy were assessed from the retrospectively collected clinical data.

Results

In a two-compartment model with Michaelis-Menten elimination, the mean maximum enzymatic conversion capacity (Vmax) value was 40% lower in DPD-deficient patients compared with controls (p < 0.001). Using a limited sampling strategy, with Vmax values calculated from 5FU concentrations at 30 or 60 minutes, significant differences were observed between DPD-deficient patients and controls at both dose levels (p < 0.001). The positive predictive value and negative predictive value for Vmax, calculated from 5FU levels at 60 minutes, were 96% and 88%, respectively, in patients treated with a single dose of 5FU 300 mg/m2. All seven DPD-deficient patients (two males and five females) who had been genotyped prior to initiation of standard 5FU-containing chemotherapy developed grade 3–4 toxicity, with one case of lethal toxicity in a female patient. No grade 4 toxicity or lethal outcome was observed in 13 DPD-deficient patients treated with reduced doses of 5FU. The average dose of 5FU in DPD-deficient patients with mild toxicity (grade ≤2) was 61 ± 16% of the normal 5FU dose (n= 10).

Conclusions

Profound differences in the elimination of 5FU could be detected between DPD-deficient patients and control patients. Pharmacokinetic 5FU profiling, using a single 5FU concentration at 60 minutes, may be useful for identification of DPD-deficient patients in order to reduce severe toxicity. Furthermore, treatment of DPD-deficient patients with standard 5FU-containing chemotherapy was associated with severe (lethal) toxicity.

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Acknowledgements

Ms Karin Heil is thanked for her skillful experimental assistance.

Conflict of interests: D. Behnke, W. Schwabe and K. Jabschinsky are employees of Oncoscreen GmbH, which performs screening for the c.1905+1G>A mutation on a commercial basis. P. Häusler is a former employee of Oncoscreen GmbH. The other authors have no conflicts of interest that are directly relevant to the content of this study.

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Authors and Affiliations

  1. Academic Medical Center, Emma Children’s Hospital and Department of Clinical Chemistry, University of Amsterdam, Amsterdam, The Netherlands

    André B. P. van Kuilenburg

  2. Clondiag GmbH, Jena, Germany

    Peter Häusler

  3. Med. Klinik III, University Hospital Großhadern, Munich, Germany

    Andreas Schalhorn

  4. Academic Medical Center, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, University of Amsterdam, Amsterdam, The Netherlands

    Michael W. T. Tanck

  5. Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands

    Johannes H. Proost

  6. Klinik für Neurologie, Asklepios Klinik St. Georg, Hamburg, Germany

    Christoph Terborg

  7. Department of Research and Development, Oncoscreen GmbH, Jena, Germany

    Detlev Behnke, Wolfgang Schwabe & Kati Jabschinsky

  8. Department of Pharmacy, Diaconessen Hospital Meppel and Bethesda Hospital Hoogeveen, Meppel, The Netherlands

    Jan Gerard Maring

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  1. André B. P. van Kuilenburg
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Correspondence to André B. P. van Kuilenburg.

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van Kuilenburg, A.B.P., Häusler, P., Schalhorn, A. et al. Evaluation of 5-Fluorouracil Pharmacokinetics in Cancer Patients with a C.1905+1G>A Mutation in DPYD by Means of a Bayesian Limited Sampling Strategy. Clin Pharmacokinet 51, 163–174 (2012). https://doi.org/10.1007/BF03257473

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