TY - JOUR
T1 - Pharmacokinetics 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 - 2019/12
Y1 - 2019/12
N2 - Capecitabine is an oral pro-drug of the anti-cancer 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.
AB - Capecitabine is an oral pro-drug of the anti-cancer 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.
UR - http://www.scopus.com/inward/record.url?scp=85075259590&partnerID=8YFLogxK
U2 - 10.1002/psp4.12474
DO - 10.1002/psp4.12474
M3 - Article
C2 - 31652031
VL - 8
SP - 940
EP - 950
JO - CPT: Pharmacometrics and Systems Pharmacology
JF - CPT: Pharmacometrics and Systems Pharmacology
IS - 12
ER -