Immunodeficiency Clinic > Drug Information
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Other Names
GS-9857, VOX
Combination formulation: Vosevi® (sofosbuvir 400mg/velpatasvir 100mg/voxilaprevir 100mg)
NS3/4A protease inhibitor
Activity
Voxilaprevir had median EC50 values of 0.2–6.6 nM against full-length or chimeric laboratory isolates and clinical isolates from subtypes 1a,
1b, 2a, 2b, 3a, 4a, 4d, 4r, 5a, 6a, 6e, and 6n.
The tablets are beige, capsule-shaped, film-coated, and debossed with “GSI” on one side and “ 3 ” on the other side.
Vosevi®:
Manufacturer states that Vosevi® tablets are not enteric-coated and are not sustained-release. Tablets can be disintegrated in water, juice, or milk with minor stirring and pressure with a spoon. A disintegrated, crushed or split tablet may have an unpleasant taste and there are no studies evaluating the pharmacokinetics of these methods of administration. (Gilead Sciences Canada, Data on File, Nov 19, 2018).
1 tablet once daily x 12 weeks.
Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18 to 85 years) analyzed, age did not have a
clinically relevant effect on the exposure to sofosbuvir, GS-331007, velpatasvir, or voxilaprevir.
No dosage adjustment of VOSEVI is required for patients with mild or moderate renal impairment. The safety and efficacy of VOSEVI have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2) or ESRD requiring hemodialysis. A dosage recommendation cannot be made for patients with severe renal impairment or end stage renal disease, due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite.
No dosage adjustment of VOSEVI is required for patients with mild hepatic impairment(Child-Pugh A). VOSEVI is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C) due to higher exposures of voxilaprevir in these patients.
- There have been post-marketing reports of hepatic decompensation and hepatic failure, including fatal outcomes, mostly in cirrhotic patients treated with HCV NS3/4A protease inhibitor-containing regimens, including sofosbuvir/velpatasvir/voxilaprevir.
- Hepatic laboratory testing should be performed as clinically indicated and patients should be monitored for signs and symptoms of hepatic decompensation such as the presence of jaundice, ascites, hepatic encephalopathy, and variceal hemorrhage.
- Discontinue the treatment with sofosbuvir/velpatasvir/voxilaprevir in patients who develop evidence of hepatic decompensation/ failure.
Food increases voxilaprevir absorption by 112 to 435%. Vosevi should be taken with food.
Velpatasvir is an inhibitor of drug transporters P-gp, BCRP, OATP1B1, OATP1B3, and OATP2B1, and its involvement in drug interactions with these transporters is primarily limited to the process of absorption. At clinically relevant concentrations, velpatasvir is not an inhibitor of hepatic transporters OATP1A2 or OCT1, renal transporters OCT2, OAT1, OAT3 or MATE1, or CYP or UGT1A1 enzymes.
Voxilaprevir is an inhibitor of drug transporters P-gp, BCRP, OATP1B1 and OATP1B3, and its involvement in drug interactions with these transporters is primarily limited to the process of absorption. At clinically relevant concentrations, voxilaprevir is not an inhibitor of hepatic transporters OCT1, renal transporters OCT2, OAT1, OAT3 or MATE1, or CYP or UGT1A1 enzymes.
Protein Binding:
>99%
Tmax:
4 hours.
Serum T½:
33 hours (28-41 hours).
Metabolism:
VOX: CYP3A4, P-gp, BCRP, OATP1B1/3 substrate. Voxilaprevir is an inhibitor of drug transporters P-gp, BCRP, OATP1B1 and OATP1B3,
and its involvement in drug interactions with these transporters is primarily limited to the process of absorption
VEL: CYP2B6, 2C8 and 3A4, P-gp, BCRP substrate. VEL is an inhibitor of drug transporters P-gp, BCRP, OATP1B1, OATP1B3, and
OATP2B1, and its involvement in drug interactions with these transporters is primarily limited to the process of absorption
SOF: Cathepsin A, CES1, HINT1, P-gp, BCRP substrate.
Excretion:
Biliary excretion (94%, 40% as parent).
HCV-infected patients
Cmax (%CV): 192 ng/mL (85.8)
AUCt (%CV): 2577ng hr/mL (73.7)
Ct (%CV): 47 ng/mL (82)
Relative to healthy subjects (n = 63), voxilaprevir AUC0-24 and Cmax were both 260% higher in HCV-infected patients.
No exposure-response relationships for efficacy were identified across exposure ranges for VOX, VEL, SOF, and GS-331007 observed in Phase 3 studies.
Voxilaprevir does not cross the blood:brain barrier.
No adequate human data are available to establish whether or not VOSEVI poses a risk to pregnancy outcomes.
Lactation
It is not known whether the components of VOSEVI and its metabolites are present in human breast milk, affect human milk production, or have effects on the breastfed infant. When the components of VOSEVI were administered to lactating rats, GS-331007 (the predominant circulating metabolite of sofosbuvir) and velpatasvir were detected in milk, while voxilaprevir was detected in the plasma of nursing pups likely
due to the presence of voxilaprevir in milk. No significant effects of any of the drugs were observed in nursing rat pups
Site-directed mutagenesis of NS3 resistance-associated substitutions showed that substitutions conferring a greater than 100-fold reduction in voxilaprevir susceptibility were A156L/T in genotype 1a, A156T/V in genotype 1b, A156L/V in genotype 2a, A156T/V in genotype 3a, and A156L/T/V in genotype 4.
The presence of baseline NS3/4A protease inhibitor, NS5A inhibitor, and nucleotide analog NS5B polymerase inhibitor resistance-associated substitutions did not alter the SVR rates for DAA-experienced subjects in the POLARIS-1 and POLARIS-4 trials who received 12 weeks of VOSEVI. For subjects treated with VOSEVI for 12 weeks, SVR12 rates in subjects with or without baseline NS3 and NS5A resistance associated substitutions in the POLARIS-1 and POLARIS-4 trials were all greater than or equal to 97%.
Cross-resistance is possible between HCV NS3/4A protease inhibitors and between HCV NS5A inhibitors by class. Sofosbuvir, velpatasvir, and voxilaprevir were each active against substitutions associated with resistance to other classes of DAAs with different mechanisms of actions (e.g., voxilaprevir was fully active against virus with NS5A resistance-associated substitutions and nucleotide analog NS5B inhibitor
resistance-associated substitutions).
Store below 30 °C (86 ºF). Dispense only in original container.
Gilead Sciences