Influence of ABCB11 and HNF4α genes on daclatasvir plasma concentration: preliminary pharmacogenetic data from the Kineti-C study

• Published in: Journal of antimicrobial chemotherapy 2017-10, Vol.72 (10), p.2846-2849
• Main Authors: Cusato, Jessica, De Nicolò, Amedeo, Boglione, Lucio, Favata, Fabio, Ariaudo, Alessandra, Mornese Pinna, Simone, Guido, Federica, Avataneo, Valeria, Carcieri, Chiara, Cariti, Giuseppe, Di Perri, Giovanni, D'Avolio, Antonio
• Format: Article
• Language: English
• Subjects: Adult; Alleles; Antiviral Agents - blood; Antiviral Agents - therapeutic use; ATP Binding Cassette Subfamily B Member 11 - drug effects; ATP Binding Cassette Subfamily B Member 11 - genetics; Female; Genotype; Hepacivirus - drug effects; Hepatitis C - drug therapy; Hepatitis C - genetics; Hepatitis C - virology; Hepatocyte Nuclear Factor 4 - drug effects; Hepatocyte Nuclear Factor 4 - genetics; Humans; Imidazoles - blood; Imidazoles - therapeutic use; Linear Models; Male; Middle Aged; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Real-Time Polymerase Chain Reaction
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkx237

Daclatasvir is an inhibitor of HCV non-structural 5A protein and is a P-glycoprotein substrate. Pharmacogenetics has had a great impact on previous anti-HCV therapies, particularly considering the association of IL-28B polymorphisms with dual therapy outcome. We investigated the association between daclatasvir plasma concentrations at 2 weeks and 1 month of therapy and genetic variants (SNPs) in genes encoding transporters and nuclear factors (ABCB1, ABCB11 and HNF4α). Allelic discrimination was achieved through real-time PCR, whereas plasma concentrations were evaluated through LC-MS/MS. Fifty-two patients were analysed, all enrolled in the Kineti-C study. HNF4α 975 C > G polymorphism was found to be associated with the daclatasvir plasma concentrations at 2 weeks (P = 0.009) and 1 month of therapy (P = 0.006). Linear regression analysis suggested that, at 2 weeks of therapy, age, baseline BMI and haematocrit were significant predictors of daclatasvir concentrations, whereas at 1 month of therapy ABCB111131 CC and HNF4α CG/GG genotypes were significant predictors of daclatasvir concentrations. These are the first and preliminary results from our clinical study focusing on daclatasvir pharmacogenetics, showing that this approach could have a role in the era of new anti-HCV therapies.