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Safety and pharmacology of gemcitabine and capecitabine in patients with advanced pancreatico-biliary cancer and hepatic dysfunction

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Abstract

Purpose

We assessed the impact of hepatic dysfunction on the safety and pharmacology of gemcitabine/capecitabine in patients with advanced pancreatico-biliary cancer.

Methods

We included 12 patients receiving 3 weekly gemcitabine 1,000 mg/m2 day 1, 8 and oral capecitabine 650 mg/m2 b.i.d. over 2 weeks until disease progression or intolerable toxicity. Patients were included into one normal hepatic function cohort [total bilirubin (TB) ≤15 μmol/L] and 3 cohorts with increasing TB (16–39, 40–80, >80 μmol/L). Three patients with a creatinine clearance <60 ml/min were also included. Patients were sampled for gemcitabine, difluoro-deoxy uridine, intracellular gemcitabine triphosphates, capecitabine, 5′-deoxy-5-fluorocytidine, 5′-deoxy-5-fluorouridine and 5-fluorouracil up to 4 h after initiation of chemotherapy on day 1, and up to 90 min on day 8. All compounds were analyzed using validated liquid chromatography–tandem mass spectrometry. Nonlinear mixed-effect modeling was used for population analysis.

Results

Hepatic dysfunction was caused by intrahepatic cholestasis in 4 out of 8 patients (50 %) and extrahepatic cholestasis in another 4 patients (50 %). Dose-limiting toxicity was increasing hyperbilirubinemia and severe neutropenia in 2 patients each. Hepatic dysfunction was not associated with dose-limiting toxicity or severe hematological or non-hematological toxicity. However, hepatic dysfunction was associated with low clearance of both gemcitabine (p = 10−3) and capecitabine (p = 10−5), and low intracellular gemcitabine triphosphate concentrations (p = 10−3).

Conclusions

Gemcitabine/capecitabine can be given at the standard dose in patients with severe hyperbilirubinemia, though the present data suggest that gemcitabine’s activity may be limited due to poor intracellular activation. In patients with severe hyperbilirubinemia, initial monotherapy with capecitabine should be considered, followed by the addition of gemcitabine with improving hyperbilirubinemia.

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Acknowledgment

The study has been supported by the Eastern Switzerland Foundation for Clinical Cancer Research (OSKK).

Author information

Authors and Affiliations

  1. Department of Medical Oncology and Hematology, Cantonal Hospital, Rorschacherstrasse 95, 9007, St. Gallen, Switzerland

    M. Joerger, D. Koeberle, F. Hitz, T. Cerny & S. Gillessen

  2. Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands

    A. D. R. Huitema, H. Rosing & J. H. Beijnen

  3. Department of Clinical Pharmacology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    J. H. Beijnen & J. H. M. Schellens

  4. Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands

    J. H. Beijnen & J. H. M. Schellens

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  1. M. Joerger
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  2. A. D. R. Huitema
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Correspondence to M. Joerger.

Electronic supplementary material

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280_2013_2327_MOESM1_ESM.tif

Supplemental Figure 1. Goodness-of-fit plots of observed (DV) versus population predicted (PRED), individual predicted (IPRED) and weighted residuals (WRES) of the plasma concentrations of gemcitabine (dFdC) (1-3), dFdU (4-6), capecitabine (CAP) (7-9), 5′-deoxy-5-fluorocytidine (DFCR) (10-12), 5′deoxy-5-fluorouridine (DFUR) (13-15) and 5-fluorouracil (5FU) (16-18). All concentrations are log-transformed. (TIFF 200 kb)

280_2013_2327_MOESM2_ESM.tif

Supplemental Figure 2. Visual predictive check (VPC) for gemcitabine and dFdU. The time axis is capped at 4 h for a clear distinction of the early time points. Blue circles represent observed data. Red lines represent the percentiles of the observed data (solid red lines = median, dashed red lines = 10 % and 90 % percentiles). The shaded regions summarize the percentiles within each bin for each simulated dataset. For each bin, the median, lower and upper percentiles are calculated, and a percentile range of these percentiles is shown as the shaded area. (TIFF 464 kb)

280_2013_2327_MOESM3_ESM.tif

Supplemental Figure 3. Visual predictive check (VPC) for capecitabine and metabolites. The time axis is capped at 6 h for a clear distinction of the early time points. Blue circles represent observed data. Red lines represent the percentiles of the observed data (solid red lines = median, dashed red lines = 10 % and 90 % percentiles). The shaded regions summarize the percentiles within each bin for each simulated dataset. For each bin, the median, lower and upper percentiles are calculated, and a percentile range of these percentiles is shown as the shaded area. (TIFF 502 kb)

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Joerger, M., Huitema, A.D.R., Koeberle, D. et al. Safety and pharmacology of gemcitabine and capecitabine in patients with advanced pancreatico-biliary cancer and hepatic dysfunction. Cancer Chemother Pharmacol 73, 113–124 (2014). https://doi.org/10.1007/s00280-013-2327-2

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  • DOI: https://doi.org/10.1007/s00280-013-2327-2

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