Pharmacokinetic Modelling of 5-FU Production from Capecitabine—A Population Study in 40 Adult Patients with Metastatic Cancer

  • Saik Urien
  • Keyvan Rezaí
  • François Lokiec


Aims: To model the biotransformation steps of 5-FU production from capecitabine and identify patient characteristics that may influence the drug disposition. Methods: Blood samples and demographic data were collected from two phase I studies in which adult patients received oral capecitabine for various malignancies. Capecitabine, 5′-deoxy-5-fluorocytidine (5′-DFCR), 5′-deoxy-5-fluorouridine (5′-DFUR) and 5-fluorouracile (5-FU) concentration-time data were analysed via a population approach using NONMEM. Results: Forty patients and 75 pharmacokinetic time-courses were available for analysis. Capecitabine pharmacokinetics was ascribed to a one compartment model from which 5′-DFCR, 5′-DFUR and 5-FU were sequentially produced. Capecitabine oral absorption was characterized by a rapid first order input (K a =2.1 ± 0.3 hr−1) with a lag time (0.28 ± 0.11 hr), but related inter-occasion (IOV) and inter-subject (ISV) variabilities for these parameters, 167% and 110%, indicated that this oral absorption was highly variable. The capecitabine CL (CL10 = 218± 18 L/hr, ISV = 18%) and 5′-DFUR elimination rate constant (K 34 = 5.3 ± 2.0 hr−1, ISV = 25%) were influenced by total bilirubin (BILT). The elimination rate constant of plasma 5-FU (K40) was 66 ± 24 hr−1 (ISV = 34%).The final pharmacokinetic model was validated using 2000 bootstrap runs and provided non-parametric statistics of the parameters (median, 2.5th and 97.5th percentiles). Conclusions: This study supported the possibility of modelling a complex sequential metabolic pathway which produces pharmacologicaly active compounds from a prodrug. Only BILT significantly influenced the pharmacokinetics but this effect was not considered as relevant for dosing adjustment.


capecitabine 5-FU population pharmacokinetics drug metabolism anticancer drugs 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Reigner, B., Blesch, K., Weidekamm, E. 2001Clinical pharmacokinetics of capecitabineClin. Pharmacokin.4085104Google Scholar
  2. Gieschke, R., Reigner, B., Blesch, K.S., Steimer, J.L. 2002Population pharmacokinetic analysis of the major metabolites of capecitabineJ Pharmacokin. Pharmacodyn.292547CrossRefGoogle Scholar
  3. Gieschke, R., Burger, H.U., Reigner, B., Blesch, K.S., Steimer, J.L 2003Population pharmacokinetics and concentration-effect relationships of capecitabine metabolites in colorectal cancer patientsBr. J. Clin. Pharmacol.55252263CrossRefPubMedGoogle Scholar
  4. Reigner, B., Verweij, J., Dirix, L., Cassidy, J., Twelves, C., Allman, D, WeideKamm, E., Roos, B., Banken, L., Utoh, M., Osterwalder, B. 1998Effect of food on the pharmacokinetics of capecitabine and its metabolites following oral administration in cancer patientsClin. Cancer Res.4941948PubMedGoogle Scholar
  5. Beal, S.L., Sheiner, L.B. 1998NONMEM User’s Guide; NONMEM project groupUniversity of CaliforniaSan Francisco, CAGoogle Scholar
  6. Ihaka, R., Gentleman, R.R. 1996A language for data analysis and graphicsJ. Comput. Graphic Stat.5299314Google Scholar
  7. Parke, J., Holford, N., Charles, B. 1999A procedure for generating bootstrap samples for the validation of nonlinear mixed-effects population modelsComput. Methods Programs Biomed591929CrossRefPubMedGoogle Scholar
  8. Poole, C., Gardiner, J., Twelves, C., Johnston, P., Harper, P., Cassidy, J, Monkhouse, J., Banken, L., Weidekamm, E., Reigner, B. 2002Effect of renal impairment on the pharmacokinetics and tolerability of capecitabine (Xeloda) in cancer patientsCancer Chemother Pharmacol.49225234CrossRefPubMedGoogle Scholar
  9. Reigner, B., Watanabe, T., Schuller, J., Lucraft, H., Sasaki, Y., Bridgewater, J, Saeki, T., McAleer, J., Kuranami, M., Poole, C., Kimura, M, Monkhouse, J., Yorulmaz, C., Weidekamm, E., Grange, S. 2003Pharmacokinetics of capecitabine (Xeloda) in Japanese and Caucasian patients with breast cancerCancer Chemother Pharmacol.52193201CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  1. 1.Pharmacology DepartmentCentre René HugueninSaint-CloudFrance
  2. 2.INSERMParisFrance

Personalised recommendations