hout cirrhosis) was assessed in 104 subjects (EXPEDITION-4). The most common adverse reactions in subjects with severe renal impairment were pruritus (17%) and fatigue (12%).
Safety in HCV/HIV-1 Co-infected Subjects
The overall safety profile in HCV/HIV-1 co-infected subjects (ENDURANCE-1 and EXPEDITION-2) was comparable to that observed in HCV mono-infected subjects.
Serum bilirubin elevations
Elevations in total bilirubin of at least 2x upper limit normal (ULN) were observed in 1.3% of subjects related to glecaprevir-mediated inhibition of bilirubin transporters and metabolism. Bilirubin elevations were asymptomatic, transient, and typically occurred early during treatment. Bilirubin elevations were predominantly indirect and not associated with ALT elevations. Direct hyperbilirubinemia was reported in 0.3% of subjects.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme:
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store
4.9 Overdose
The highest documented doses administered to healthy volunteers is 1,200 mg once daily for 7 days for glecaprevir and 600 mg once daily for 10 days for pibrentasvir. Asymptomatic serum ALT elevations (>5x ULN) were observed in 1 out of 70 healthy subjects following multiple doses of glecaprevir (700 mg or 800 mg) once daily for ≥ 7 days. In case of overdose, the patient should be monitored for any signs and symptoms of toxicities (see section 4.8). Appropriate symptomatic treatment should be instituted immediately. Glecaprevir and pibrentasvir are not significantly removed by haemodialysis.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Direct-acting antiviral, ATC code: not yet assigned
Mechanism of action
Maviret is a fixed-dose combination of two pan-genotypic, direct-acting antiviral agents, glecaprevir (NS3/4A protease inhibitor) and pibrentasvir (NS5A inhibitor), targeting multiple steps in the HCV viral lifecycle.
Glecaprevir
Glecaprevir is a pan-genotypic inhibitor of the HCV NS3/4A protease, which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication.
Pibrentasvir
Pibrentasvir is a pan-genotypic inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. The mechanism of action of pibrentasvir has been characterized based on cell culture antiviral activity and drug resistance mapping studies.
Antiviral activity
The EC50 values of glecaprevir and pibrentasvir against full-length or chimeric replicons encoding NS3 or NS5A from laboratory strains are presented in Table 5.
Table 5. Activity of glecaprevir and pibrentasvir against HCV genotypes 1-6 replicon cell lines
NA = not available
The in vitro activity of glecaprevir was also studied in a biochemical assay, with similarly low IC50 values across genotypes.
EC50 values of glecaprevir and pibrentasvir against chimeric replicons encoding NS3 or NS5A from clinical isolates are presented in Table 6.
Table 6. Activity of glecaprevir and pibrentasvir against transien |
