Pharmacokinetics of capecitabine and four metabolites in a heterogeneous population of cancer patients: a comprehensive analysis

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.