Abstract

III-31 Juan Pablo Cayun Pellizaris Association between genetic, adverse events and pharmacokinetics in testicular cancer patients. Juan Cayún (1), Berta Cerda (2), Ángela Roco (3) Luis Quiñones (3), Patrick Nolain (4), Marion Bourdoncle (4), Jean-Baptiste Woillard (4). (1, 3) Laboratory of Chemical Carcinogenesis and Pharmacogenetics, University of Chile, Chile. (2) Cancer national institute of Chile, Chile. (4) Inserm U850, University of Limoges, France Objectives: To study the association of the genetics variants, pharmacokinetics of PEB chemotherapy and adverse events related with chemotherapy. Methods: We recruited 63 patients with testicular cancer. Patients were treated with cisplatin, etoposide and Bleomycin (PEB). Genetics polymorphisms on GSTM1 null, GSTT1 null, CYP3A4*1B and BLMH (A1450G) were detected in these patients through PCR-RFLP 1. A pharmacokinetics preliminary study of cisplatin was realized on 9 patients. Analysis statistical was performance with STATA 11.1 and pharmacokinetics data was analyzed with Monolix 4.2 (parametric) 2 and Pmetrics (non parametric) 3. Association between polymorphisms and toxicity was investigated using univariate and multivariate logistic regressions and with PK parameters using Mann Whitney tests. Results: In the univariate and multivariate analysis, we founded that GSTM1 null patients have a decreased risk of developing grade 3-4 leucopenia (OR=0.20, 95% IC 0.04-1.04; p=0.041), while BLMH A/G patients have a major risk of developing grade 3-4 leucopenia (OR=5.35, 95% IC 0.99-28.89; p=0.036) and grade 3-4 hematological toxicity (OR=57.67, 95% IC 2.14-27.35; p=0.001). A two-compartment model best described the data of cisplatin. In Monolix, the parameters values for CL and V1 were (mean ± S.D.) 7.44 ± 1.7 L/hr and 4.16 ± 3.1 L respectively and allowed a good description of the data with a bias between observed and expected concentrations of 0.236 ± 1.21. For Pmetrics, addition of an absorption phase considering a metabolic transformation (median [min-max], Ke=0.86 [0.003-3.25], V1 = 6.85 [1.2-50], Ka = 2.5 [1.4-4.9]) allowed a better description of the data with a bias between observed and expected concentrations of 0.02 ± 0.50. No association between PK parameters and genetic polymorphisms was observed using neither Monolix nor Pmetrics results. Conclusions: Our findings show that GSTM1 present patients and BLMH A/G patients are more likely to develop grade 3-4 leucopenia. Hematological toxicity is more frequent in BLMH A/G patients. Nevertheless no association between PK parameters and genetic polymorphisms was shown. This is preliminary evidence in pharmacogenetics of PEB chemotherapy in testicular patients. Fondecyt Grant 1140434