Drug-Drug Interaction between the Direct-Acting Antiviral Regimen of Ombitasvir-Paritaprevir-Ritonavir plus Dasabuvir and the HIV Antiretroviral Agent Dolutegravir or Abacavir plus Lamivudine.

The direct-acting antiviral regimen of 25 mg ombitasvir-150 mg paritaprevir-100 mg ritonavir once daily (QD) plus 250 mg dasabuvir twice daily (BID) is approved for the treatment of hepatitis C virus genotype 1 infection, including patients coinfected with human immunodeficiency virus. This study was performed to evaluate the pharmacokinetic, safety, and tolerability effects of coadministering the regimen of 3 direct-acting antivirals with two antiretroviral therapies (dolutegravir or abacavir plus lamivudine). Healthy volunteers (n = 24) enrolled in this phase I, single-center, open-label, multiple-dose study received 50 mg dolutegravir QD for 7 days or 300 mg abacavir plus 300 mg lamivudine QD for 4 days, the 3-direct-acting-antiviral regimen for 14 days, followed by the 3-direct-acting-antiviral regimen with dolutegravir or abacavir plus lamivudine for 10 days. Pharmacokinetic parameters were calculated to compare combination therapy with 3-direct-acting-antiviral or antiretroviral therapy alone, and safety/tolerability were assessed throughout the study. Coadministration of the 3-direct-acting-antiviral regimen increased the geometric mean maximum plasma concentration (Cmax) and the area under the curve (AUC) of dolutegravir by 22% (central value ratio [90% confidence intervals], 1.219 [1.153, 1.288]) and 38% (1.380 [1.295, 1.469]), respectively. Abacavir geometric mean Cmax and AUC values decreased by 13% (0.873 [0.777, 0.979]) and 6% (0.943 [0.901, 0.986]), while those for lamivudine decreased by 22% (0.778 [0.719, 0.842]) and 12% (0.876 [0.821, 0.934]). For the 3-direct-acting-antiviral regimen, geometric mean Cmax and AUC during coadministration were within 18% of measurements made during administration of the 3-direct-acting-antiviral regimen alone, although trough concentrations for paritaprevir were 34% (0.664 [0.585, 0.754]) and 27% (0.729 [0.627, 0.847]) lower with dolutegravir and abacavir-lamivudine, respectively. All study treatments were generally well tolerated, with no evidence of increased rates of adverse events during combination administration. These data indicate that the 3-direct-acting-antiviral regimen can be administered with dolutegravir or abacavir plus lamivudine without dose adjustment.

Khatri A ，Trinh R ，Zhao W ，Podsadecki T ，Menon R ... -  《-》

Pharmacokinetic Evaluation of Darunavir Administered Once or Twice Daily in Combination with Ritonavir or the Three-Direct-Acting Antiviral Regimen of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir in Adults Coinfected with Hepatitis C and Human Immunode

The three-direct-acting antiviral (3D) regimen containing ombitasvir, paritaprevir, ritonavir, and dasabuvir with or without ribavirin (RBV) is approved for treatment of hepatitis C virus (HCV) genotype 1 (GT1)/human immunodeficiency virus type 1 (HIV-1) coinfection. Results of a pharmacokinetic substudy of 3D and darunavir are presented. HCV/HIV-1-coinfected subjects were randomized to maintain an antiretroviral regimen with darunavir at 800 mg once daily (QD) or switched to a regimen with darunavir at 600 mg twice daily (BID). On study day 1, subjects received 3D and RBV plus darunavir for 12 weeks. Pharmacokinetic parameters were compared for darunavir and ritonavir with and without 3D (week 4 and day -1). Pharmacokinetic parameters of 3D were compared to historical data. Ten subjects received darunavir QD, and 12 subjects received darunavir BID. The central value ratios (90% confidence interval [CI]) for maximum concentrations (Cmax), area under the plasma concentration-time curve between 0 and 24 h postdose (AUC24), and trough plasma concentration at 24 h postdose (C24) of darunavir administered QD with 3D versus administration of darunavir alone were 0.92 (0.72, 1.18), 0.83 (0.71, 0.98), and 0.64 (0.44, 0.93), respectively. The ratios (90% CI) for darunavir Cmax, AUC12, and C12 administered BID with 3D were 0.92 (0.76, 1.12), 0.88 (0.73, 1.05), and 0.73 (0.58, 0.92), respectively. Exposures of 3D were similar to or slightly lower than those in historical data. All darunavir trough concentrations (Ctrough) associated with an HIV-1 RNA level of >40 copies/ml were above the darunavir 50% effective concentration (EC50) of 550 ng/ml for resistant virus. In conclusion, the 3D regimen with darunavir QD or BID did not affect darunavir Cmax and AUC, whereas the darunavir Ctrough decreased. Changes in pharmacokinetic parameters of 3D were not considered clinically significant. Episodes of intermittent HIV-1 viremia were infrequent and were not associated with darunavir Ctrough values below 550 ng/ml. (This study has been registered at ClinicalTrials.gov under identifier NCT01939197.).

King JR ，Khatri A ，Trinh R ，Viani RM ，Ding B ，Zha J ，Menon R ... -  《-》

Drug-Drug Interaction of Omeprazole With the HCV Direct-Acting Antiviral Agents Paritaprevir/Ritonavir and Ombitasvir With and Without Dasabuvir.

Paritaprevir (administered with low-dose ritonavir), ombitasvir, and dasabuvir are direct-acting antiviral agents administered as combination regimens for the treatment of chronic hepatitis C virus infection. Drug-drug interactions between 2D (ombitasvir/paritaprevir/ritonavir) or 3D (ombitasvir/paritaprevir/ritonavir and dasabuvir) regimens and omeprazole, a CYP2C19 substrate and acid-reducing agent, were evaluated in 24 healthy volunteers. Subjects received omeprazole (40 mg once daily) on day 1 and days 20-24 and the 2D or 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily ± dasabuvir 250 mg twice daily) on days 6-24. Compared with omeprazole alone, coadministration with the 2D or 3D regimen decreased omeprazole geometric mean Cmax and AUCt values by 40% to 50%. Ombitasvir, dasabuvir, and ritonavir mean exposures showed <10% change, and paritaprevir mean exposures showed <20% change when the 2D or 3D regimen was administered with omeprazole compared with administration without omeprazole. Although no a priori dose adjustment is needed, a higher omeprazole dose should be considered if clinically indicated when coadministered with the 2D or 3D regimen. No dose adjustment is required for the 2D or 3D regimen when administered with omeprazole, other acid-reducing agents, or CYP2C19 inhibitors.

Polepally AR ，Dutta S ，Hu B ，Podsadecki TJ ，Awni WM ，Menon RM ... -  《Clinical Pharmacology in Drug Development》

Drug-Drug Interactions Between the Anti-Hepatitis C Virus 3D Regimen of Ombitasvir, Paritaprevir/Ritonavir, and Dasabuvir and Eight Commonly Used Medications in Healthy Volunteers.

Polepally AR ，King JR ，Ding B ，Shuster DL ，Dumas EO ，Khatri A ，Chiu YL ，Podsadecki TJ ，Menon RM ... -  《-》

Evaluation of Drug-Drug Interactions Between Hepatitis C Antiviral Agents Ombitasvir, Paritaprevir/Ritonavir, and Dasabuvir and HIV-1 Protease Inhibitors.

Guidelines for the treatment of human immunodeficiency virus (HIV) infection consistently recommend initiation of antiretroviral therapy in patients with hepatitis C virus (HCV)/HIV-1 coinfection. Therefore, potential drug interactions between antiretroviral drugs and HCV direct-acting antiviral agents (DAAs) must be carefully considered. The objective of this investigation was to evaluate the compatibility of a novel combination of DAAs (the 3D regimen) with commonly prescribed HIV-1 protease inhibitors (PIs). Five phase 1, multiple-dose, open-label pharmacokinetic studies were performed in 144 healthy volunteers. Participants in each study were randomly assigned 1:1 into cohorts assessing the effects of the steady-state 3D regimen on steady-state HIV-1 PIs or vice versa. The 3D regimen comprised ombitasvir (25 mg once daily), paritaprevir/ritonavir (150/100 mg once daily), and dasabuvir (250 or 400 mg twice daily). The HIV-1 PIs assessed included atazanavir, darunavir, and lopinavir (administered with ritonavir). Safety, tolerability, and pharmacokinetic parameters were assessed to evaluate the compatibility of the drug regimens. Coadministration of the 3D regimen with the evaluated HIV-1 PIs was generally well tolerated in healthy volunteers. Morning administration of atazanavir (300 mg once daily) and darunavir regimens exhibited no clinically meaningful drug interactions with the 3D regimen. However, owing to higher paritaprevir and/or ritonavir exposures, evening administration of atazanavir (300 mg) plus ritonavir (100 mg) or lopinavir/ritonavir (800/200 mg) with the 3D regimen is not recommended. The 3D regimen can be coadministered with morning atazanavir and darunavir regimens. However, evening atazanavir plus ritonavir and lopinavir/ritonavir regimens are not recommended in combination with the 3D regimen.

Khatri A ，Dutta S ，Wang H ，Podsadecki T ，Trinh R ，Awni W ，Menon R ... -  《-》