Influence of CYP2C19 and ABCB1 Genetic Polymorphisms on Voriconazole Levels in Haematological Patients

Ref ID: 18771

Author:

L. Baietto, BSc, MSc – PhD student, A. D’Avolio, BSc, MSc, SM – Researcher, J. Cusato, BSc, MSc – Biologist, C. Marra, BSc – Student, M. Simiele, BSc, MSc – PhD student, F. G. De Rosa, MD – Associate Professor, G. Di Perri, MD, DTM & H, PhD – Profess

Author address:

Univ. of Turin, Turin, Italy.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Objectives: Voriconazole (VRC) is a triazole antifungal with excellent oral bioavailability and highly variable non linear pharmacokinetics. It is well known that genotype CYP2C19(*2) cause different rate of clearance dividing population in poor and extensive metabolizers. We aimed at investigating whether single nucleotide polymorphisms (SNPs) of CYP2C19 and P-Glycoprotein Coding Gene (ABCB1) might influence VRC levels in haematological patients. Methods: 17 haematological patients (9 male, 8 female) in therapy with oral VRC (200 mg twice daily) were enrolled. Blood samples were obtained immediately before drug intake (Ctrough), at steady state (after 7 days of therapy). Plasma concentrations were assayed using a validated HPLC-MS method. Genotyping for SNPs of ABCB1 (C3435T, C1236T, G2677T) and of CYP2C19 (CYP2C19*2) was done using RT-PCR allelic discrimination assay. Mann Whitney and Spearman Test were used to analyze variables. Results: Median [Interquartile Range] age, weight and Ctrough were 47 years [17-67], 67 Kg [50-81] and 1.51 mg/L [1.29-2.93] respectively. 14 patients (82.4%) had Ctrough>1 mg/L and 7 patients (41.2%) had Ctrough>2 mg/L (efficacy cut-off); 1 patient (5.9%) had Ctrough>5.5 mg/L (toxicity cut-off). VRC Ctrough were statistically significantly higher in patients with homozygote mutate genotype for ABCB1 C3435T (p=0.035). Patients having homozygote mutate genotype for CYP2C19*2 had higher VRC Ctrough but the difference was not statistically significant, probably for the low number of patients. CYP2C19*2 was related to Ctrough>2 mg/L (p = 0.04) and ABCB1 C1236T and G2677G SNPs were related to Ctrough>5.5 mg/L (p= 0.001 and p= 0.035, respectively). Conclusions: We found an influence of ABCB1 SNPs on VRC Ctrough which may explain the high inter-patient variability in VRC plasmatic levels. Future studies in a larger sample size are warranted to confirm these data and to understand the clinical usefulness of VRC pharmacogenomics.

Abstract Number: A-1937

Conference Poster: y

Conference Year: 2012

Link to conference website: NULL

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