etic analysis of HCV-infected subjects, 86% higher glecaprevir and 54% higher pibrentasvir AUC were observed for subjects with end stage renal disease, with or without dialysis, compared to subjects with normal renal function. Larger increases may be expected when unbound concentration is considered.
Overall, the changes in exposures of Maviret in HCV-infected subjects with renal impairment with or without dialysis were not clinically significant.
Hepatic impairment
At the clinical dose, compared to non-HCV infected subjects with normal hepatic function, glecaprevir AUC was 33% higher in Child-Pugh A subjects, 100% higher in Child-Pugh B subjects, and increased to 11-fold in Child-Pugh C subjects. Pibrentasvir AUC was similar in Child-Pugh A subjects, 26% higher in Child-Pugh B subjects, and 114% higher in Child-Pugh C subjects. Larger increases may be expected when unbound concentration is considered.
Population pharmacokinetic analysis demonstrated that following administration of Maviret in HCV-infected subjects with compensated cirrhosis, exposure of glecaprevir was approximately 2-fold and pibrentasvir exposure was similar to non-cirrhotic HCV-infected subjects. The mechanism for the differences between glecaprevir exposure in chronic Hepatitis C patients with or without cirrhosis is unknown.
5.3 Preclinical safety data
Glecaprevir and pibrentasvir were not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity, chromosome aberration using human peripheral blood lymphocytes and in vivo rodent micronucleus assays. Carcinogenicity studies with glecaprevir and pibrentasvir have not been conducted.
No effects on mating, female or male fertility, or early embryonic development were observed in rodents at up to the highest dose tested. Systemic exposures (AUC) to glecaprevir and pibrentasvir were approximately 63 and 102 times higher, respectively, than the exposure in humans at the recommended dose.
In animal reproduction studies, no adverse developmental effects were observed when the components of Maviret were administered separately during organogenesis at exposures up to 53 times (rats; glecaprevir) or 51 and 1.5 times (mice and rabbits, respectively; pibrentasvir) higher than the human exposures at the recommended dose of Maviret. Maternal toxicity (anorexia, lower body weight, and lower body weight gain) with some embryofoetal toxicity (increase in post-implantation loss and number of resorptions and a decrease in mean foetal body weight), precluded the ability to eva luate glecaprevir in the rabbit at clinical exposures. There were no developmental effects with either compound in rodent peri/postnatal developmental studies in which maternal systemic exposures (AUC) to glecaprevir and pibrentasvir were approximately 47 and 74 times higher, respectively, than the exposure in humans at the recommended dose. Unchanged glecaprevir was the main component observed in the milk of lactating rats without effect on nursing pups. Pibrentasvir was the only component observed in the milk of lactating rats without effect on nursing pups.
6. Pharmaceutical particulars
6.1 List of excipients
Tablet core
Copovidone (Type K 28)
Vitamin E (tocopherol) polyethylene glycol succinate
Silica, colloidal anhydrous
Propylene glycol monocaprylate (Type II)
Croscarmellose sodium
Sodium stearyl fumarate
Film coating
Hypromellose 2910 (E464)
Lactose monohydrate
Titanium |
