title: Efavirenz pharmacogenetics in a cohort of Italian patients.
abstract: The pharmacogenetics and pharmacokinetics of efavirenz (EFV) have been widely studied, although data in the Italian population are limited. Single nucleotide polymorphisms (SNPs) in the CYP2B6 gene have been associated with increased EFV plasma concentrations and central nervous system toxicity. The aim of this work was to evaluate EFV plasma exposure according to SNPs in genes involved in drug metabolism and elimination in a cohort of Italian HIV-1-positive patients treated with EFV. Plasma samples were used to measure EFV concentrations at 12h after intake (C12) by a validated HPLC/PDA system. Whole blood was used to identify SNPs in ABCB1, MRP2, CYP2B6, CYP2A6, UGT2B7, NR1I2 (PXR), NR1I3 (CAR) and HNF4α by real-time PCR. The association between SNPs and EFV plasma levels was evaluated through non-parametric tests. Among 201 patients, the median EFV C12 was 2618.5ng/mL. No significant associations were found for MRP2, CYP2A6, UGT2B7, PXR and CAR SNPs; conversely, an association of CYP2B6 516G>T, ABCB1 3435C>T and 2677G>T, and HNF4α 975C>G polymorphisms with EFV C12 was observed. In multivariate analysis, only CYP2B6 516 TT and ABCB1 3435 TT genotypes were independently associated with an EFV C12 of >4000ng/mL (toxicity cut-off). This study confirmed the role of CYP2B6 and ABCB1 polymorphisms, showed a relationship with HNF4α, and the lack of association of CYP2A6, UGT2B7, NR1I2 and NR1I3 SNPs on EFV plasma exposure. Data regarding some of the studied SNPs are the first obtained in an Italian cohort of HIV patients and lead to a global vision about EFV pharmacogenetics.
authors.affiliation: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy. Electronic address: jessica.cusato@yahoo.it.
authors.forename: Jessica
authors.initials: J
authors.lastname: Cusato
authors.affiliation: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy; Hospital Pharmacy, Maria Vittoria Hospital, ASL TO2, Turin, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tomasello
authors.affiliation: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy; CoQua Lab, Academic spin-off of the University of Turin, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Simiele
authors.affiliation: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Calcagno
authors.affiliation: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonora
authors.affiliation: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Marinaro
authors.affiliation: Hospital Pharmacy, Maria Vittoria Hospital, ASL TO2, Turin, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Leggieri
authors.affiliation: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Allegra
authors.affiliation: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Perri
authors.affiliation: Unit of Infectious Diseases, University of Turin, Department of Medical Sciences, Amedeo di Savoia Hospital, Turin, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Avolio
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000493:pharmacokinetics*; D000090702:Constitutive Androstane Receptor; D003521:Cyclopropanes; D005260:Female; D015497:HIV-1; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010949:Plasma / Q000737:chemistry*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D000090702:Constitutive Androstane Receptor; D003521:Cyclopropanes; C000716327:NR1I3 protein, human; C098320:efavirenz
keywords: ABCB1; CYP2B6; HNF4α; Pharmacokinetics; SNP