Pharmaco*kinetics of Capecitabine and Four Metabolites in a Heterogeneous Population of Cancer Patients: A Comprehensive Analysis (2024)

Jacobs, B. A. W., Deenen, M. J., Joerger, M., Rosing, H., de Vries, N., Meulendijks, D., Cats, A., Beijnen, J. H., Schellens, J. H. M., & Huitema, A. D. R. (2019). Pharmaco*kinetics of Capecitabine and Four Metabolites in a Heterogeneous Population of Cancer Patients: A Comprehensive Analysis. CPT: Pharmacometrics and Systems Pharmacology, 8(12), 940-950. https://doi.org/10.1002/psp4.12474

Jacobs, Bart A W ; Deenen, Maarten J ; Joerger, Markus et al. / Pharmaco*kinetics of Capecitabine and Four Metabolites in a Heterogeneous Population of Cancer Patients : A Comprehensive Analysis. In: CPT: Pharmacometrics and Systems Pharmacology. 2019 ; Vol. 8, No. 12. pp. 940-950.

@article{0c741fb3a040421099eee6957b12cc62,

title = "Pharmaco*kinetics of Capecitabine and Four Metabolites in a Heterogeneous Population of Cancer Patients: A Comprehensive Analysis",

abstract = "Capecitabine is an oral prodrug of the anticancer drug 5-fluorouracil (5-FU). The primary aim of this study was to develop a pharmaco*kinetic model for capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine (dFCR), 5'-deoxy-5-fluorouridine (dFUR), 5-FU, and fluoro-β-alanine (FBAL) using data from a heterogeneous population of cancer patients (n = 237) who participated in seven clinical studies. A four-transit model adequately described capecitabine absorption. Capecitabine, dFCR, and FBAL pharmaco*kinetics were well described by two-compartment models, and dFUR and 5-FU were subject to flip-flop pharmaco*kinetics. Partial and total gastrectomy were associated with a significantly faster capecitabine absorption resulting in higher capecitabine and metabolite peak concentrations. Patients who were heterozygous polymorphic for a genetic mutation encoding dihydropyrimidine dehydrogenase, the DPYD*2A mutation, demonstrated a 21.5% (relative standard error 11.2%) reduction in 5-FU elimination. This comprehensive population model gives an extensive overview of capecitabine and metabolite pharmaco*kinetics in a large and heterogeneous population of cancer patients.",

author = "Jacobs, {Bart A W} and Deenen, {Maarten J} and Markus Joerger and Hilde Rosing and {de Vries}, Niels and Didier Meulendijks and Annemieke Cats and Beijnen, {Jos H} and Schellens, {Jan H M} and Huitema, {Alwin D R}",

note = "{\textcopyright} 2019 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.",

year = "2019",

month = oct,

day = "25",

doi = "10.1002/psp4.12474",

language = "English",

volume = "8",

pages = " 940--950",

journal = "CPT: Pharmacometrics and Systems Pharmacology",

issn = "2163-8306",

publisher = "Nature Publishing Group",

number = "12",

}

Jacobs, BAW, Deenen, MJ, Joerger, M, Rosing, H, de Vries, N, Meulendijks, D, Cats, A, Beijnen, JH, Schellens, JHM & Huitema, ADR 2019, 'Pharmaco*kinetics of Capecitabine and Four Metabolites in a Heterogeneous Population of Cancer Patients: A Comprehensive Analysis', CPT: Pharmacometrics and Systems Pharmacology, vol. 8, no. 12, pp. 940-950. https://doi.org/10.1002/psp4.12474

Pharmaco*kinetics of Capecitabine and Four Metabolites in a Heterogeneous Population of Cancer Patients: A Comprehensive Analysis. / Jacobs, Bart A W; Deenen, Maarten J; Joerger, Markus et al.
In: CPT: Pharmacometrics and Systems Pharmacology, Vol. 8, No. 12, 25.10.2019, p. 940-950.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Pharmaco*kinetics of Capecitabine and Four Metabolites in a Heterogeneous Population of Cancer Patients

T2 - A Comprehensive Analysis

AU - Jacobs, Bart A W

AU - Deenen, Maarten J

AU - Joerger, Markus

AU - Rosing, Hilde

AU - de Vries, Niels

AU - Meulendijks, Didier

AU - Cats, Annemieke

AU - Beijnen, Jos H

AU - Schellens, Jan H M

AU - Huitema, Alwin D R

N1 - © 2019 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

PY - 2019/10/25

Y1 - 2019/10/25

N2 - Capecitabine is an oral prodrug of the anticancer drug 5-fluorouracil (5-FU). The primary aim of this study was to develop a pharmaco*kinetic model for capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine (dFCR), 5'-deoxy-5-fluorouridine (dFUR), 5-FU, and fluoro-β-alanine (FBAL) using data from a heterogeneous population of cancer patients (n = 237) who participated in seven clinical studies. A four-transit model adequately described capecitabine absorption. Capecitabine, dFCR, and FBAL pharmaco*kinetics were well described by two-compartment models, and dFUR and 5-FU were subject to flip-flop pharmaco*kinetics. Partial and total gastrectomy were associated with a significantly faster capecitabine absorption resulting in higher capecitabine and metabolite peak concentrations. Patients who were heterozygous polymorphic for a genetic mutation encoding dihydropyrimidine dehydrogenase, the DPYD*2A mutation, demonstrated a 21.5% (relative standard error 11.2%) reduction in 5-FU elimination. This comprehensive population model gives an extensive overview of capecitabine and metabolite pharmaco*kinetics in a large and heterogeneous population of cancer patients.

AB - Capecitabine is an oral prodrug of the anticancer drug 5-fluorouracil (5-FU). The primary aim of this study was to develop a pharmaco*kinetic model for capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine (dFCR), 5'-deoxy-5-fluorouridine (dFUR), 5-FU, and fluoro-β-alanine (FBAL) using data from a heterogeneous population of cancer patients (n = 237) who participated in seven clinical studies. A four-transit model adequately described capecitabine absorption. Capecitabine, dFCR, and FBAL pharmaco*kinetics were well described by two-compartment models, and dFUR and 5-FU were subject to flip-flop pharmaco*kinetics. Partial and total gastrectomy were associated with a significantly faster capecitabine absorption resulting in higher capecitabine and metabolite peak concentrations. Patients who were heterozygous polymorphic for a genetic mutation encoding dihydropyrimidine dehydrogenase, the DPYD*2A mutation, demonstrated a 21.5% (relative standard error 11.2%) reduction in 5-FU elimination. This comprehensive population model gives an extensive overview of capecitabine and metabolite pharmaco*kinetics in a large and heterogeneous population of cancer patients.

U2 - 10.1002/psp4.12474

DO - 10.1002/psp4.12474

M3 - Article

C2 - 31652031

SN - 2163-8306

VL - 8

SP - 940

EP - 950

JO - CPT: Pharmacometrics and Systems Pharmacology

JF - CPT: Pharmacometrics and Systems Pharmacology

IS - 12

ER -

Jacobs BAW, Deenen MJ, Joerger M, Rosing H, de Vries N, Meulendijks D et al. Pharmaco*kinetics of Capecitabine and Four Metabolites in a Heterogeneous Population of Cancer Patients: A Comprehensive Analysis. CPT: Pharmacometrics and Systems Pharmacology. 2019 Oct 25;8(12): 940-950. doi: 10.1002/psp4.12474