era does not affect medicinal product transport by these proteins.
Special populations
Elderly
Based on population pharmacokinetic analysis of data from Phase 3 clinical studies, a 10 year increase or decrease in age from 54 years (median age in the Phase 3 studies) would results in <10% change in dasabuvir exposures. There is no pharmacokinetic information in patients >75 years.
Sex or body weight
Based on population pharmacokinetic analysis of data from Phase 3 clinical studies, female subjects would have approximately 14 to 30% higher dasabuvir exposures than male subjects. A 10 kg change in body weight from 76 kg (median weight in the Phase 3 studies) would result in <10% change in dasabuvir exposures.
Race or ethnicity
Based on population pharmacokinetic analysis of data from Phase 3 clinical studies, Asian subjects had 29% to 39% higher dasabuvir exposures than non-Asian subjects.
Renal impairment
Pharmacokinetics of the combination of ombitasvir 25 mg, paritaprevir 150 mg, and ritonavir 100 mg, with dasabuvir 400 mg were eva luated in subjects with mild (CrCl: 60 to 89 ml/min), moderate (CrCl: 30 to 59 ml/min) and severe (CrCl: 15 to 29 ml/min) renal impairment, relative to subjects with normal renal function.
In subjects with mild, moderate and severe renal impairment, dasabuvir mean AUC values were 21% higher, 37% higher and 50% higher, respectively. Dasabuvir M1 AUC values were 6% lower, 10% lower, and 13% lower, respectively.
The changes in dasabuvir exposures in subjects with mild, moderate and severe renal impairment are not considered to be clinically significant. Exviera has not been studied in patients on dialysis (see section 4.2).
Hepatic impairment
Pharmacokinetics of the combination of dasabuvir 400 mg, with ombitasvir 25 mg, paritaprevir 200 mg, and ritonavir 100 mg were eva luated in subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, relative to subjects with normal hepatic function.
In subjects with mild, moderate and severe hepatic impairment, dasabuvir AUC values were 17% higher, 16% lower and 325% higher, respectively. The AUC values of dasabuvir M1 metabolite were unchanged, 57% lower, and 77% higher, respectively. Plasma protein binding of dasabuvir and its M1 metabolite were not meaningfully different in subjects with hepatic impairment compared to normal control subjects.
The changes in dasabuvir exposures in subjects with mild and moderate hepatic impairment are not considered clinically significant. The safety and efficacy of Exviera and ombitasvir/paritaprevir/ritonavir have not been established in HCV-infected patients with moderate hepatic impairment (Child-Pugh B) (see section 4.2).
Paediatric population
The pharmacokinetics of Exviera with ombitasvir/paritaprevir/ritonavir in paediatric patients has not been investigated (see section 4.2).
5.3 Preclinical safety data
Dasabuvir was 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 rat micronucleus assays.
Dasabuvir was not carcinogenic in a 6-month transgenic mouse study up to the highest dosage tested (2 g/kg/day), resulting in dasabuvir AUC exposures approximately 39-fold higher than those in humans at the recommended dose of 500 mg (250 mg twice daily).
The carcinogenicity study of dasabuvir in rats is ongoing.
Dasabuvir had no effects on embryo-f |
