PP122—Regulation of human leukocyte antigen expression and nevirapine-induced adverse drug reactions in a malawian hiv-positive population

Abstract

2013 e53 University; Clinical Pharmacology and Toxicology Service, Geneva University Hospitals, Geneva, Switzerland; CharlesBruneau Cancer Center, CHU Sainte-Justine Research Center; Department of Pediatrics, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center; Department of Pharmacology; and Department of Pediatrics, Charles-Bruneau Cancer Center, University of Montreal, Montreal, Canada Introduction: Cytochrome P 450 enzymes (CYPs) were presumed to play a role in the oxidation of intermediate metabolites of busulfan (Bu). In vitro elucidation of involvement of CYPs in the oxidation of Bu metabolites is cumbersome due to the volatile nature of tetrahydrothiophene and nonavailability of sensitive quantitation methods. This study is aimed at exploring the association of CYP2C9, CYP2C19, CYP2B6, FMO genotypes, and sulfolane (Su) levels in children undergoing hematopoietic stem cell transplantation (HSCT).The relation of genotypes with the outcomes of HSCT was also explored. Patients (or Materials) and Methods: Sixty-six children receiving IV Bu-based myeloablative conditioning regimen were genotyped for common functional variant alleles in CYP2C9 (*2 and *3), CYP2C19 (*2 and *17), FMO3 (rs2266780, rs2266782 and rs1736557) and CYP2B6 (*5 and *9). Plasma levels of Bu and its metabolite Su were measured after dose 9 from a subset of 44 patients for whom plasma samples after dose 9 were available. The ratio of Bu to Su was taken as a metabolic ratio (MR) to compare among genotype groups. The MRs (Bu/Su), Bu and Su levels between different genotype groups were compared using nonparametric tests. The distribution of age, and gender between the groups was compared using t test and chisquare test, respectively. Cumulative incidence of overall survival and event-free survival were estimated using Kaplan-Meier curves and log-rank test was used to compare the difference between genotype groups or groups divided on the basis of MR, in a univariate analysis. Multivariate analysis was performed using cox-regression analysis. Results: Higher metabolic ratios (MRs, Bu/Su) were observed in CYP2C9*2 and *3 allele carriers (mean [SD], 7.8 [3.6] Vs 4.4 [2.2]; P = 0.003). Lower event-free survival was seen in patients with MR above the median 5 (40% vs 79%; P = 0.009) and carrying reduced function alleles of CYP2B6 (40% vs 84%; P = 0.005). Conclusion: This study suggests the role of the CYP2C9 in the oxidation reactions of THT and CYP genotypes along with Bu MRs to be important at predicting outcomes of Bu based myeloablative conditioning before HSCT. Disclosure of Interest: None declared.