%0 Journal Article %A Mohamad Shebley %A Jinrong Liu %A Olga Kavetskaia %A Jens Sydor %A Sonia M de Morais %A Volker Fischer %A Marjoleen JMA Nijsen %A Daniel AJ Bow %T Mechanisms and Predictions of Drug-Drug Interactions of the Hepatitis C Virus 3-Direct Acting Antiviral (3D) Regimen: Paritaprevir/Ritonavir, Ombitasvir and Dasabuvir %D 2017 %R 10.1124/dmd.116.074518 %J Drug Metabolism and Disposition %P dmd.116.074518 %X To assess drug-drug interaction (DDI) potential for the 3 direct-acting antiviral (3D) regimen of ombitasvir, dasabuvir and paritaprevir, in vitro studies profiled drug metabolizing enzyme and transporter interactions. Using mechanistic static and dynamic models, DDI potential was predicted for CYP3A, CYP2C8, UGT1A1, OATP1B1/1B3, BCRP and P-gp. Perpetrator static model DDI predictions for metabolizing enzymes were within 2-fold of the clinical observations but for drug transporters, additional PBPK modeling was necessary to achieve the same. When assessing perpetrator interactions, ritonavir, is responsible for the strong increase in exposure of sensitive CYP3A substrates while paritaprevir (OATP1B1/1B3 inhibitor) increases greatly the exposure of sensitive OATP1B1/1B3 substrates. The 3D regimen drugs are UGT1A1 inhibitors and are predicted to moderately increase plasma exposure of sensitive UGT1A1 substrates. Paritaprevir, ritonavir and dasabuvir are BCRP inhibitors. Victim DDI predictions were qualitatively in line with the clinical observations. Plasma exposures of the 3D regimen were reduced by strong CYP3A inducers (paritaprevir and ritonavir; major CYP3A substrates), but not impacted by strong CYP3A4 inhibitors since ritonavir (CYP3A inhibitor) is already present in the regimen. Strong CYP2C8 inhibitors increase plasma exposure of dasabuvir (major CYP2C8 substrate), OATP1B1/1B3 inhibitors increase the plasma exposure of paritaprevir (OATP1B1/1B3 substrate), and P-gp or BCRP inhibitors (all compound are substrates of P-gp and/or BCRP) increase plasma exposure of the 3D regimen. Overall, comprehensive mechanistic assessment of compound disposition along with mechanistic and PBPK approaches to predict victim and perpetrator DDI liability, may enable better clinical management of non-studied drug combinations with the 3D regimen. %U https://dmd.aspetjournals.org/content/dmd/early/2017/05/08/dmd.116.074518.full.pdf