In vitro enzyme and transporters victim data summary of paritaprevir, ritonavir, ombitasvir, dasabuvir, and M1

Enzyme or Transporter 
(Endpoint or Unit)ParitaprevirRitonavirOmbitasvirDasabuvirM1
CYP2C8 (% contribution)∼60<10
CYP3A4 (% contributiona)∼100, <50 with ritonavir∼100, <50 due to autoinhibition∼100, <10 with ritonavir∼30, <10 with ritonavir∼100, <10 with ritonavir
P-gp/MDR-1 (net efflux ratiob)132644632
BCRP (net efflux ratio)522
OATP1B1, Km (µM)c0.21.3
OATP1B3, Km (µM)0.11.7
  • P450 contribution results are from incubations with individual recombinant human isoforms. Results for dasabuvir are based on chemical inhibition in human liver microsomes, and those for ritonavir are based on correlation analysis in human liver microsomes. Dashes indicate not a substrate based on in vitro studies. MDCKII, Madin-Darby canine kidney II.

  • a CYP3A4 contribution is shown as individual drug in vitro results first, followed by the overall contribution within the 3D regimen where ritonavir is coadministered.

  • b Efflux ratio from MDCKII cells overexpressing P-gp or BCRP (normalized for efflux in wild-type MDCKII cells).

  • c The Michaelis–Menton kinetics constant (Km) was generated after initial active uptake screening studies (see the Materials and Methods).