Publikation
Pharmacokinetics of Capecitabine and Four Metabolites in a Heterogeneous Population of Cancer Patients: A Comprehensive Analysis.
Wissenschaftlicher Artikel/Review - 20.11.2019
Jacobs Bart A W, Deenen Maarten J, Joerger Markus, Rosing Hilde, de Vries Niels, Meulendijks Didier, Cats Annemieke, Beijnen Jos H, Schellens Jan H M, Huitema Alwin D R
PubMed
DOI
Kontakt
Zitation
Art
Zeitschrift
Veröffentlichungsdatum
eISSN (Online)
Seiten
Kurzbeschreibung/Zielsetzung
Capecitabine is an oral prodrug of the anticancer drug 5-fluorouracil (5-FU). The primary aim of this study was to develop a pharmacokinetic 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 pharmacokinetics were well described by two-compartment models, and dFUR and 5-FU were subject to flip-flop pharmacokinetics. 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 pharmacokinetics in a large and heterogeneous population of cancer patients.