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.
References:
[1]. Roco Á, Quiñones L, Agúndez JAG, García-Martín E, Squicciarini V, Miranda C, Garay J, Farfán N, Saavedra I, Cáceres D, Ibarra C and Varela N. Frequencies of 23 Functionally Significant Variant Alleles Related with Metabolism of Antineoplastic Drugs in the Chilean Population: Comparison with Caucasian and Asian Populations. Front. Gene. 3:229, 2012.
[2]. Lavielle M, Mentré F. Estimation of population pharmacokinetic parameters of saquinavir in HIV patients with the MONOLIX software. J Pharmacokinet Pharmacodyn. 2007 Apr; 34(2):229-49. Epub 2007 Jan 9.
[3]. Neely MN, van Guilder MG, Yamada WM, Schumitzky A, Jelliffe RW. Accurate Detection of Outliers and Subpopulations with Pmetrics, a Nonparametric and Parametric Pharmacometric Modeling and Simulation Package for R. Therapeutic Drug Monitoring. 2012; 34(4): 467-476.
Reference: PAGE 23 (2014) Abstr 3043 [www.page-meeting.org/?abstract=3043]
Poster: Drug/Disease modeling - Oncology