Pharmacogenetics of the anti-HCV drug sofosbuvir: a preliminary study

• Published in: Journal of antimicrobial chemotherapy Vol. 73; no. 6; pp. 1659 - 1664
• Main Authors: Cusato, Jessica, De Nicolò, Amedeo, Boglione, Lucio, Favata, Fabio, Ariaudo, Alessandra, Mornese Pinna, Simone, Carcieri, Chiara, Guido, Federica, Avataneo, Valeria, Cariti, Giuseppe, Di Perri, Giovanni, D’Avolio, Antonio
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.06.2018
• ISSN: 0305-7453; 1460-2091; 1460-2091
• DOI: 10.1093/jac/dky053

Abstract Background Sofosbuvir is a potent nucleotide HCV NS5B polymerase inhibitor that is also a P-glycoprotein (encoded by the ABCB1 gene) and breast cancer resistance protein (encoded by the ABCG2 gene) substrate. Concerning previous anti-HCV therapies, pharmacogenetics had a significant impact, particularly considering the association of interleukin28B polymorphisms with dual-therapy (ribavirin + pegylated IFN) outcomes. Objectives In this work, we investigated the association between sofosbuvir and its prevalent metabolite (GS-331007) plasma concentrations at 1 month of therapy and genetic variants (SNPs) in genes encoding transporters and nuclear factors (ABCB1, ABCG2 and HNF4α) related to sofosbuvir transport. Patients and methods Allelic discrimination was performed through real-time PCR, whereas plasma concentrations were evaluated through liquid chromatography. One hundred and thirteen patients were enrolled. Results Sofosbuvir concentrations were below the limit of quantification since the drug was converted into its GS-331007 metabolite. ABCB1 2677 G>T (P = 0.044) and HNF4α 975 C>G (P = 0.049) SNPs were associated with GS-331007 metabolite plasma concentrations. In linear multivariate analysis, liver stiffness, insulin resistance, baseline haemoglobin and haematocrit and SNPs in the ABCB1 gene (3435 CT/TT and 1236 TT genotypes) were significant predictors of GS-331007 concentrations. Furthermore, we performed sub-analyses considering the anti-HCV concomitant drug and HCV genotype, identifying specific polymorphisms associated with GS-331007 plasma concentrations: ABCB1 3435 C>T and HNF4α975 C>G in patients treated with daclatasvir, ABCB1 2677 G>T with ledipasvir and ABCB1 3435 C>T, ABCB1 2677 G>T, ABCG2 421 C>A and ABCG2 1194 + 928 C>A with ribavirin. Conclusions In this study we suggested sofosbuvir GS-331007 metabolite plasma levels were affected by variants in the ABCB1 and HNFα genes.