Pharmacokinetics and exposure-effect relationships of capecitabine in elderly patients with breast or colorectal cancer

Abstract

Purpose: The aims of the present study were (1) to investigate the impact of great age on pharmacokinetics of capecitabine and its metabolites and (2) to evaluate the exposure-effect relationship of capecitabine in elderly patients.

Methods: Data collected from 20 elderly patients (75-92 years old) with breast or colorectal cancer who received oral capecitabine were analyzed. In order to study the old age effect on pharmacokinetics, data collected from two phase I studies involving 40 younger adults (<75 years old) with metastatic cancer who received oral capecitabine were added in the database. The population pharmacokinetic analysis was based on a four-compartment model describing the sequence of capecitabine and three of its metabolites.

Results: The absorption rate constant was found lower in the oldest patient group (≥75 years) compared with the youngest group, and the constant rate elimination of the 5-fluorouracil metabolite was found decreased over time (i.e., after 2 consecutive weeks of capecitabine administration). This time effect was not found different between the two age groups. In elderly patients, the exposure-safety analysis showed, from the second cycle of chemotherapy, significantly higher median exposures of capecitabine and its metabolites (5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine and 5-fluorouracil) in patients who experienced hand-foot syndrome compared with patients who did not.

Conclusion: This study puts forward new arguments for the treatment of elderly cancer patients who could benefit from capecitabine chemotherapy with acceptable toxicity.

Trial registration: ClinicalTrials.gov NCT00812864.

Figures

Figure 1

Compartmental model describing the pharmacokinetics of capecitabine and its four metabolites. Abbreviations: ka: absorption rate constant; tlag: lag-time; V1: apparent distribution volume of capecitabine; CL10 and CL12: apparent capecitabine clearances; k23: intercompartmental rate constant of 5′-DFCR; k34: intercompartmental rate constant of 5′-DFUR; k45: intercompartmental rate constant of 5-FU; k50: elimination rate constant of FBAL. *These two metabolites were measured only in one subgroup of patients; 5′-DFCR was measured only in patients of the two phase I study (<75 years) and FBAL was measured only in patients of the CAPAGEC trial (≥75 years).

Figure 2

Comparisons of the area under the concentration-time curve (AUC; μmol.h/L) of (a) capecitabine, (b) 5′DFCR, (c) 5′DFUR,(d) 5 FU and (e) FBAL in the second cycle of treatment, between patients who experienced hand-foot syndrome (HFS+) and who did not experience (HFS−).