onavir are highly bound to plasma proteins. Plasma protein binding is not meaningfully altered in subjects with renal or hepatic impairment. The blood to plasma concentration ratios in humans ranged from 0.6 to 0.8 indicating that ombitasvir and paritaprevir were preferentially distributed in the plasma compartment of whole blood. Ombitasvir was approximately 99.9% bound to human plasma proteins. Paritaprevir was approximately 97-98.6% bound to human plasma proteins. Ritonavir was greater than 99% bound to human plasma proteins.
In vitro data indicate that paritaprevir is a substrate for the human hepatic uptake transporters, OATP1B1 and OATP1B3.
Biotransformation
Ombitasvir
Ombitasvir is metabolised via amide hydrolysis followed by oxidative metabolism. Following a 25 mg single dose of 14C-ombitasvir given alone, unchanged parent drug accounted for 8.9% of total radioactivity in human plasma; a total of 13 metabolites were identified in human plasma. These metabolites are not expected to have antiviral activity or off-target pharmacologic activity.
Paritaprevir
Paritaprevir is metabolised predominantly by CYP3A4 and to a lesser extent CYP3A5. Following administration of a single 200 mg/100 mg oral dose of 14C paritaprevir /ritonavir to humans, the parent drug was the major circulating component, accounting for approximately 90% of the plasma radioactivity. At least 5 minor metabolites of paritaprevir have been identified in circulation that accounted for approximately 10% of plasma radioactivity. These metabolites are not expected to have antiviral activity.
Ritonavir
Ritonavir is predominantly metabolised by CYP3A and to a lesser extent, by CYP2D6. Nearly the entire plasma radioactivity after a single 600 mg dose of 14C-ritonavir oral solution in humans was attributed to unchanged ritonavir.
Elimination
Ombitasvir
Following dosing of ombitasvir/paritaprevir/ritonavir with or without dasabuvir, mean plasma half-life of ombitasvir was approximately 21 to 25 hours. Following a single 25 mg dose of 14C- ombitasvir approximately 90% of the radioactivity was recovered in faeces and 2% in urine. Unchanged parent drug accounted for 88% of total radioactivity recovered in faeces, indicating that biliary excretion is a major elimination pathway for ombitasvir.
Paritaprevir
Following dosing of ombitasvir/paritaprevir /ritonavir with or without dasabuvir, mean plasma half-life of paritaprevir was approximately 5.5 hours. Following a 200 mg 14C -paritaprevir dose with 100 mg ritonavir, approximately 88% of the radioactivity was recovered in faeces with limited radioactivity (8.8%) in urine. Metabolism as well as biliary excretion of parent drug contribute to the elimination of paritaprevir.
Ritonavir
Following dosing of ombitasvir/paritaprevir /ritonavir, mean plasma half-life of ritonavir was approximately 4 hours. Following a 600 mg dose of 14C -ritonavir oral solution, 86.4% of the radioactivity was recovered in the faeces and 11.3% of the dose was excreted in the urine.
In vitro interaction data
Ombitasvir and paritaprevir do not inhibit organic anion transporter (OAT1) in vivo and are not expected to inhibit organic cation transporters (OCT1 and OCT2), organic anion transporters (OAT3), or multidrug and toxin extrusion proteins (MATE1 and MATE2K) at clinically relevant concentrations. Ritonavir does not in
