Km1 = 7.1 µM; Vmax1 = 0.0001 nmol/min/pmol; CYP2C8 Km = 79.1 µM; Vmax = Unlikely 0.001 nmol/min/pmol; P-gp, Contradictory: AUC unchanged when BCRP Ombitasvir was not a administered with cyclosporine; substrate of P-gp or Cmax decreased by 23% when BCRP mediated efflux administered with atazanavir in vitro, but mice lacking these transporters had increased exposure levels CYP2C8 CYP2C8 inhibitor Confirmed (AUC increased 1025% quercetin inhibited by gemfibrozil) in vitro metabolism in human liver microsomes by 60% CYP3A4 CYP3A inhibitor Confirmed (AUC increased 42% by ketoconazole ketoconazole; decreased 70% by inhibited in vitro carbamazepine metabolism in human liver microsomes by 30% P-gp Inhibited by Confirmed C (AUC decreased 21% LY335979 and by OATP1B1 inhibitor atazanavir cyclosporin A in and 30% by inhibitor cyclosporin) BCRP Inhibited by BCRP inhibitor K0143 BCRP Inhibited by BCRP Not tested M1 inhibitor K0143 Km = 1.30 µM Km = 1.71 µM Data taken from reports RD13893 and RD13811 a: Studies in KO mice indicate that OATP transporters † affect the distribution between liver and plasma. Table 14: paritaprevir/ombitasvir/dasabuvir as perpetrators Nonclinical Clinical Relevance for Findings Enzyme or
Km1 = 7.1 µM; Vmax1 = 0.0001 nmol/min/pmol; CYP2C8 Km = 79.1 µM; Vmax = 0.001 nmol/min/pmol; Unlikely P-gp, BCRP Contradictory: Ombitasvir was not a substrate of P-gp or BCRP mediated efflux in vitro, but mice lacking these transporters had increased exposure levels AUC unchanged when with cyclosporine; Cmax decreased by 23% when with atazanavir CYP2C8 CYP2C8 inhibitor quercetin inhibited in vitro metabolism in human liver microsomes by 60% Confirmed (AUC increased 1025% by gemfibrozil) CYP3A4 CYP3A inhibitor ketoconazole inhibited in vitro metabolism in human liver microsomes by 30% Confirmed (AUC increased 42% by ketoconazole; decreased 70% by carbamazepine P-gp Inhibited by LY335979 and cyclosporin A in Confirmed C (AUC decreased 21% by OATP1B1 inhibitor atazanavir and 30% by inhibitor cyclosporin) BCRP Inhibited by BCRP inhibitor K0143 M1 BCRP Inhibited by BCRP inhibitor K0143 Not tested Km = 1.30 µM Km = 1.71 µM † Data taken from reports RD13893 and RD13811 a: Studies in KO mice indicate that OATP transporters affect the distribution between liver and plasma. Table 14: paritaprevir/ombitasvir/dasabuvir as perpetrators for Enzyme or Nonclinical Findings Clinical Relevance administered administered
auspar-paritaprevir-ritonavir-ombitasvir-dasabuvir-as-sodium-salt-and-ribavirin-170324.docx