Aldaz A.1, ZufÃa L.1, Bueno L,2 Sayar O2.
(1) Pharmacy Department. ClÃnica Universidad de Navarra, Pamplona, Spain
Objectives: Capecitabine, a fluorouracil (5FU) prodrug, has proven efficacy in those tumors in which fluoruracil is effective. To be active, it requires an intracellular activation by phosphorylation. Two enzymes are important in its disposition: cytidin deaminase and dihydropyrimidin dehydrogenase. Capecitabine is increasingly used due to the oral administration even if it is more expensive than 5FU.The main problems with its use are toxicity and treatment adherence. It is therefore necessary to optimise its administration, and the same exposition goals as with 5FU can be applied. Therefore a population pharmacokinetic model must be developed and incorporated to a bayesian prediction programme in order to select the best dosing schedule to achieve the pharmacological goal.With this aim, the following objective was established: To characterise the population pharmacokinetics of capecitabine.
Methods: Capecitabine was administered orally to 7 patients at standard doses. Plasma samples were collected at 10 different sampling times. Capecitabine, 5DFUR, 5 FU and FUH2 were quantified by HPLC(1). A population pharmacokinetic model was performed using NONMEM version VI. Model discrimination was based on the minimum value of the objective function and visual inspection of goodness of fit plots. Due to the small number of patients, and the different profiles of Capecitabine and its metabolites, volume of the latter was fixed to one for estimation issues
Results:Capecitabine plasma concentration profile and its metabolites were properly described using a five-compartment model, with first order absorption and Alag time. This model allows a good fit for both concentrations of capecitabine and its metabolites in the 7 patients with the exception of the fifth patient FUH2.The model estimated high variability in Ka, Alag time, Volume and Clearance of Capecitabine.
Conclusions: The resulting model is a good proposal for estimating the optimal strategy of sampling in a larger number of patients to allow at a later stage to obtain a more robust model for clinical use. The oncologists increasingly demand tools that optimize chemotherapeutic treatments
References:
[1] L. Zufía, A.Aldaz, J. Giraldez. Simple determination of capecitabine and its metabolites by liquid chromatography with ultraviolet detection in a single injection. J. Chromatogr. B 2004; 809: 51-58.
Reference: PAGE 21 () Abstr 2614 [www.page-meeting.org/?abstract=2614]
Poster: Oncology