Vitamin D pathway genetic variants are able to influence sofosbuvir and its main metabolite pharmacokinetics in HCV mono-infected patients

• Published in: Infection, genetics and evolution genetics and evolution, 2018-06, Vol.60, p.42-47
• 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: Article
• Language: English
• Subjects: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase - genetics; 25-Hydroxyvitamin D3 1-alpha-Hydroxylase - metabolism; Antiviral Agents - pharmacokinetics; Antiviral Agents - therapeutic use; Calcitriol; Chronic hepatitis C; DAA; Drug Monitoring; Female; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - epidemiology; Humans; Male; Middle Aged; Pharmacogenetics; Polymorphism, Single Nucleotide - genetics; Receptors, Calcitriol - genetics; Receptors, Calcitriol - metabolism; Retrospective Studies; SNP; Sofosbuvir - pharmacokinetics; Sofosbuvir - therapeutic use; Therapeutic drug monitoring; Vitamin D - metabolism; Vitamin D-Binding Protein - genetics; Vitamin D-Binding Protein - metabolism; Vitamin D3 24-Hydroxylase - genetics; Vitamin D3 24-Hydroxylase - metabolism
• ISSN: 1567-1348; 1567-7257
• DOI: 10.1016/j.meegid.2018.02.016

Vitamin D levels and genetic variants were associated with drug outcome/toxicity and concentrations. The plasma exposure of GS-331007, the main sofosbuvir metabolite, has been related to SVR. We evaluated the impact of polymorphisms in genes (CYP27B1, CYP24A1, VDBP and VDR) related to vitamin D pathway on sofosbuvir and GS-331007 plasma levels in HCV mono-infected patients at one month of treatment. Polymorphisms were investigated through real-time PCR; drug plasma quantification was performed through a UHPLC-MS/MS method. GS-331007 levels were associated with CYP24A1rs2248359 and VDRCdx2 variants in all the analyzed patients and linear regression analysis showed that sex, body mass index, HCV genotype, baseline estimated glomerular filtration rate, VDRCdx2AG/GG and CYP27B1-1260TT genotypes significantly predict concentrations. We performed sub-analyses considering the HCV genotype and the concomitant drug, identifying polymorphisms associated with GS-331007 concentrations. This is the first study focusing on vitamin D pathway gene variants and DAAs concentrations, but further studies are required. [Display omitted] •Vitamin D is a modulator of biological processes, including immune system.•Genetic polymorphisms involved in vitamin D pathway influenced drug concentrations.•Vitamin D gene SNPs significantly predict sofosbuvir metabolite concentrations.•Pharmacogenetics could be helpful in the prediction of good response patients.