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Gastric cancer (GC) is often diagnosed at later stages due to the lack of specificity of symptoms associated with the neoplasm, causing high mortality rates worldwide. The first line of adjuvant and neoadjuvant treatment includes cytotoxic fluoropyrimidines and platin-containing compounds which cause the formation of DNA adducts. The clinical outcome with these antineoplastic agents depends mainly on tumor sensitivity, which is conditioned by the expression level of the drug targets and the DNA-repair system enzymes. In addition, some germ line polymorphisms, in genes linked to drug metabolism and response to chemotherapy, have been associated with poor responses and the development of adverse effects, even with fatal outcomes in GC patients. The identification of genomic biomarkers, such as individual gene polymorphisms or differential expression patterns of specific genes, in a patient-by-patient context with potential clinical application is the main focus of current pharmacogenomic research, which aims at developing a rational and personalized therapy (i.e., a therapy that ensures maximum efficacy with no predictable side effects). However, because of the future application of genomic technologies in the clinical setting, it is necessary to establish the prognostic value of these genomic biomarkers with genotype-phenotype association studies and to evaluate their prevalence in the population under treatment. These issues are important for their cost-effectiveness evaluation, which determines the feasibility of using these medical genomic research products for GC treatment in the clinical setting.

Objective: To develop and internally validate a population pharmacokinetic model for gemcitabine and its metabolite 2',2'-difluorodeoxyuridine (dFdU); and to evaluate its predictive perfomance for personalizing the dosage used in cancer patients., Methods: Gemcitabine and dFdU plasma concentrations were determined in 18 cancer patients. A 2-compartment pharmacokinetic model was implemented in the NONMEN VI program to determine the appropriate pharmacokinetic parameters. The power to identify the parameters was assessed by parametric bootstrap, and the internal model validation was performed using nonparametric bootstrap and visual and numerical predictive check methods. The final predictive performance of the model was assessed for accuracy and precision during the first (a priori) and second (a posteriori) chemotherapy cycles., Results: The mean and interpatient variability of gemcitabine and dFdU clearance was 2.70 L/min (31.0%) and 0.0515 L/min (35.8%), respectively. The estimated distribution volume at steady state was 30 L for gemcitabine and 238 L for dFdU. Internal validation confirmed that the population pharmacokinetic model was appropriate for describing the plasma concentrations of gemcitabine and dFdU over time, as well as its variability in the study population. The accuracy and precision of a posteriori gemcitabine plasma concentrations improved by 67% and 46%, respectively, compared to the a priori prediction., Conclusion: The population pharmacokinetic model adequately characterised the gemcitabine and dFdU plasma concentrations in the study population over time, and can be used to accurately and precisely optimise gemcitabine dosing regimens in cancer patients., (Copyright © 2011 SEFH. Published by Elsevier Espana. All rights reserved.)

Capecitabine is the first drug in a new fluoropyrimidine class that offers distinct characteristics. On one hand its oral administration mimics continuous fluorouracil infusion while remaining convenient with higher patient acceptance and compliance rates and avoiding intravenous administration-associated complications and financial costs. On other hand it provides intra-tumour selective activation, thus potentially facilitating local management and therefore improved anti-tumour activity as well as reduced systemic toxicity. The concentration of thymidine phosphorylase an enzyme essential for capecitabine activation in tumour cells increases after exposure to cytotoxics such as taxanes, cyclophosphamide, gemcitabine or vinorelbine, which results in synergistic activity. It has been tried both as monotherapy and in combination with other chemotherapy agentsâboth in first-line regimes and in previously treated patients against metastatic colorectal and breast cancer, results being very good in terms of efficacy and tolerability.