Pharmacokinetics of Capecitabine and Four Metabolites in a Heterogeneous Population of Cancer Patients: A Comprehensive Analysis

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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

14 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)940-950
Aantal pagina's11
TijdschriftCPT: Pharmacometrics and Systems Pharmacology
Volume8
Nummer van het tijdschrift12
DOI's
StatusGepubliceerd - 1 dec. 2019
Extern gepubliceerdJa

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