5 to 5 μg/mL. At steady-state the exposures ratio of M1 to dasabuvir is approximately 0.6. Taking into account the protein binding and in vitro activity of M1 against HCV genotype 1, its contribution to efficacy is expected to be similar to that of dasabuvir. In addition, M1 is a substrate of the hepatic uptake transporters OATP family and OCT1 and thus, the hepatocyte concentration and thereby contribution to efficacy, may be larger than dasabuvir.
Biotransformation
Dasabuvir is predominantly metabolised by CYP2C8 and to a lesser extent by CYP3A. Following a 400 mg 14C-dasabuvir dose in humans, unchanged dasabuvir was the major component (approximately 60%) of drug related radioactivity in plasma. Seven metabolites were identified in plasma. The most abundant plasma metabolite was M1, which represented 21% of drug-related radioactivity (AUC) in circulation following single dose; it's formed via oxidative metabolism predominantly by CYP2C8.
Elimination
Following dosing of dasabuvir with ombitasvir/ paritaprevir /ritonavir, mean plasma half-life of dasabuvir was approximately 6 hours. Following a 400 mg 14C-dasabuvir dose, approximately 94% of the radioactivity was recovered in faeces with limited radioactivity (approximately 2%) in urine. Unchanged dasabuvir accounted for 26.2% and M1 for 31.5% of the total dose in faeces. M1 is mainly cleared through direct biliary excretion with the contribution of UGT-mediated glucuronidation and, to a small extent, oxidative metabolism.
Dasabuvir does not inhibit organic anion transporter (OAT1) in vivo and is not expected to inhibit organic cation transporters (OCT2), organic anion transporters (OAT3), or multidrug and toxin extrusion proteins (MATE1 and MATE2K) at clinically relevant concentrations; therefore, Exviera 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 signif
