itro, slow metabolic turnover of velpatasvir by CYP2B6, CYP2C8, and CYP3A4 was observed. Drugs that are inducers of P-gp or moderate to potent inducers of CYP2B6, CYP2C8, or CYP3A4 may significantly reduce plasma concentrations of sofosbuvir and velpatasvir, leading to potentially reduced therapeutic effects. Concomitant use is not recommended. The FDA-labeling states that sofosbuvir; velpatasvir may be administered with P-gp, BCRP, and CYP inhibitors. Additionally, velpatasvir is an inhibitor of the drug transporters P-gp, BCRP, OATP1B1, OATP1B3, and OAT2B1. Coadministration with substrates of these transporters may increase their exposure. Drug interactions with these transporters is primarily limited to the process of absorption.
Velpatasvir is not an inhibitor of OATP1A2, OCT1, OCT2, OAT1, OAT3, MATE1, or CYP or UGT1A1 enzymes. Sofosbuvir and GS-331007 are not inhibitors of P-gp, BCRP, OATP1B1, OATP1B3, and OCT1. GS-331007 is not an inhibitor of OAT1, OAT3, OCT2, and MATE1. Sofosbuvir and GS-331007 are not inhibitors or inducers of CYP or UGT1A1 enzymes.
Oral Route
Sofosbuvir: After oral administration, the time to reach maximum plasma concentrations (Tmax) is approximately 0.5 to 1 hours for the parent drug sofosbuvir. The mean steady state concentrations (AUC) and the maximum plasma concentrations (Cmax) for sofosbuvir and GS-331007 in patients infected with hepatitis C are similar to those observed in healthy subjects. Administration of a single dose with a moderate fat meal (600 kcal, 30% fat) increased the mean systemic exposure of sofosbuvir by 60%, while a high fat meal (1000 kcal, 50% fat) resulted in an increased systemic exposure of sofosbuvir by 78%.
Velpatasvir: After oral administration, the time to reach maximum plasma concentrations (Tmax) is approximately 3 hours. Relative to healthy subject, the velpatasvir AUC and Cmax were 37% and 42% lower, respectively, in HCV-infected patients. Administration of a single dose with a moderate fat meal (600 kcal, 30% fat) increased the mean systemic exposure of velpatasvir by 34%, while a high fat meal (1000 kcal, 50% fat) resulted in an increased systemic exposure of velpatasvir by 21%. |
