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Pharmacokinetics and pharmacogenetics of capecitabine and its metabolites following replicate administration of two 500 mg tablet formulations

  • Clinical Trial Report
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Abstract

Purpose

To describe concentration versus time profiles of capecitabine and its metabolites 5′-DFUR, 5′-DFCR and 5-FU, depending on tablet formulation and on frequent and/or relevant genetic polymorphisms of cytidine deaminase, dihydropyrimidine dehydrogenase, thymidylate synthase and methylenetetrahydrofolate reductase (MTHFR).

Methods

In 46 cancer patients on chronic capecitabine treatment, who voluntarily participated in the study, individual therapeutic doses were replaced on four consecutive mornings by the study medication. The appropriate number of 500 mg test (T) or reference (R) capecitabine tablets was given in randomly allocated sequences TRTR or RTRT (replicate design). Average bioavailability was assessed by ANOVA.

Results

Thirty female and 16 male patients suffering from gastrointestinal or breast cancer (mean age 53.4 years; mean dose 1739 mg) were included. The T/R ratios for AUC0–t(last) and C max were 96.7 % (98 % CI 90.7–103.2 %) and 87.2 % (98 % CI 74.9–101.5 %), respectively. Within-subject variability for AUC0–t(last) and C max (coefficient of variation for R) was 16.5 and 30.2 %, respectively. Similar results were seen for all metabolites. No serious adverse events occurred. For the MTHFR C677T (rs1801133) genotype, an increasing number of 677C alleles showed borderline correlation with an increasing elimination half-life of capecitabine (p = 0.043).

Conclusions

The extent of absorption was similar for T and R, but the rate of absorption was slightly lower for T. While such differences are not considered as clinically relevant, formal bioequivalence criteria were missed. A possible, probably indirect role of the MTHFR genotype in pharmacokinetics of capecitabine and/or 5-FU should be investigated in further studies.

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Acknowledgments

We would like to thank Kathi Krüsemann for her excellent support in pharmacogenetic analyses. The following persons and their teams are acknowledged for their contribution to the conductance of the study in the participating study centers: Paola Di Gion; Dr. med. Jochen Graff; Agnieszka Gruszfeld-Jagiello MD, PhD; Prof. Dr. med. Walter E. Haefeli; Judit Kapocsi MD, PhD; Prof. István LÁNG MD, PhD, DSc; Vertkin Arkady Lvovich; PD Dr. med. habil. Dr. rer. nat. Jürgen E. Metzner; Renata Surma-Wlodarczyk, MD.

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Authors and Affiliations

  1. Department of Pharmacology, University of Cologne, Cologne, Germany

    Christian Queckenberg, V. Erlinghagen & U. Fuhr

  2. Clinical Trials Centre Cologne, Medical Faculty, University of Cologne, Gleueler Str. 269, 50935, Cologne, Germany

    Christian Queckenberg

  3. Synthon BV, Nijmegen, The Netherlands

    B. C. M. Baken & S. H. G. Van Os

  4. M.A.R.C.O. GmbH & Co. KG, Düsseldorf, Germany

    M. Wargenau

  5. Quinta-Analytica S.r.o., Prague, Czech Republic

    V. Kubeš, R. Peroutka & V. Novotný

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  1. Christian Queckenberg
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  4. S. H. G. Van Os
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Correspondence to Christian Queckenberg.

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Conflict of interest

All costs of the study were covered by Synthon BV, Nijmegen, the Netherlands. Baken BCM and Van Os SHG are employees of Synthon BV. All other researchers conducted their contribution to the study as work for hire for Synthon. The authors declare not to have further conflicts of interest.

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Queckenberg, C., Erlinghagen, V., Baken, B.C.M. et al. Pharmacokinetics and pharmacogenetics of capecitabine and its metabolites following replicate administration of two 500 mg tablet formulations. Cancer Chemother Pharmacol 76, 1081–1091 (2015). https://doi.org/10.1007/s00280-015-2840-6

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  • DOI: https://doi.org/10.1007/s00280-015-2840-6

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