Dasabuvir

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Rajeev M Menon - One of the best experts on this subject based on the ideXlab platform.

  • Effects of chronic kidney disease stage 4, end-stage renal disease, or dialysis on the plasma concentrations of ombitasvir, paritaprevir, ritonavir, and Dasabuvir in patients with chronic HCV infection: pharmacokinetic analysis of the phase 3 RUBY-I
    European journal of clinical pharmacology, 2018
    Co-Authors: Diana L. Shuster, Rajeev M Menon, Amit Khatri, Bifeng Ding, Eric Cohen, Melissa Jewett, Daniel E. Cohen, Jiuhong Zha
    Abstract:

    Purpose To characterize the pharmacokinetics of ombitasvir, paritaprevir, ritonavir, Dasabuvir, and ribavirin in hepatitis C virus (HCV)-infected patients with chronic kidney disease stage 4 (CKD4) or end-stage renal disease (ESRD), including those on dialysis, in the open-label phase 3 RUBY-I and RUBY-II studies. Methods Patients (n = 18 CKD4, n = 68 ESRD) received ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily ± Dasabuvir 250 mg twice daily ± ribavirin 200 mg once daily for 12 or 24 weeks. Intensive pharmacokinetic samples were collected from ten patients; sparse samples were collected from all patients. Arterial and venous samples were collected from three patients during hemodialysis. Area under the plasma concentration-time curve (AUC) was estimated using noncompartmental analyses for intensive data, and steady-state trough concentrations (Ctrough) were obtained from the sparse data. Pharmacokinetic results from RUBY-I and RUBY-II were compared empirically to historical data. Results The AUC values of ombitasvir, paritaprevir, ritonavir, and Dasabuvir were comparable between CKD4 and ESRD patients and were within the range of values observed in historical studies; dialysis had no effect on drug exposures. Ribavirin was extracted during hemodialysis but had similar exposures on dialysis and non-dialysis days. Individual steady-state Ctrough values for each drug overlapped between CKD4 and ESRD patients, and values in both groups were similar to historical values. Conclusion Plasma concentrations of ombitasvir, paritaprevir, ritonavir, and Dasabuvir were not altered by renal impairment or dialysis, suggesting these agents can be administered to HCV-infected CKD4 or ESRD patients, including those on dialysis, without dose adjustment. Trial registration Clinicaltrials.gov identifiers: NCT02207088 (RUBY-I) and NCT02487199 (RUBY-II).

  • Effects of chronic kidney disease stage 4, end-stage renal disease, or dialysis on the plasma concentrations of ombitasvir, paritaprevir, ritonavir, and Dasabuvir in patients with chronic HCV infection: pharmacokinetic analysis of the phase 3 RUBY-I
    European Journal of Clinical Pharmacology, 2018
    Co-Authors: Diana L. Shuster, Rajeev M Menon, Amit Khatri, Bifeng Ding, Eric Cohen, Melissa Jewett, Hong Li, Daniel E. Cohen
    Abstract:

    To characterize the pharmacokinetics of ombitasvir, paritaprevir, ritonavir, Dasabuvir, and ribavirin in hepatitis C virus (HCV)-infected patients with chronic kidney disease stage 4 (CKD4) or end-stage renal disease (ESRD), including those on dialysis, in the open-label phase 3 RUBY-I and RUBY-II studies. Patients (n = 18 CKD4, n = 68 ESRD) received ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily ± Dasabuvir 250 mg twice daily ± ribavirin 200 mg once daily for 12 or 24 weeks. Intensive pharmacokinetic samples were collected from ten patients; sparse samples were collected from all patients. Arterial and venous samples were collected from three patients during hemodialysis. Area under the plasma concentration-time curve (AUC) was estimated using noncompartmental analyses for intensive data, and steady-state trough concentrations (Ctrough) were obtained from the sparse data. Pharmacokinetic results from RUBY-I and RUBY-II were compared empirically to historical data. The AUC values of ombitasvir, paritaprevir, ritonavir, and Dasabuvir were comparable between CKD4 and ESRD patients and were within the range of values observed in historical studies; dialysis had no effect on drug exposures. Ribavirin was extracted during hemodialysis but had similar exposures on dialysis and non-dialysis days. Individual steady-state Ctrough values for each drug overlapped between CKD4 and ESRD patients, and values in both groups were similar to historical values. Plasma concentrations of ombitasvir, paritaprevir, ritonavir, and Dasabuvir were not altered by renal impairment or dialysis, suggesting these agents can be administered to HCV-infected CKD4 or ESRD patients, including those on dialysis, without dose adjustment. Clinicaltrials.gov identifiers: NCT02207088 (RUBY-I) and NCT02487199 (RUBY-II)

  • Pharmacokinetics of Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir in Healthy Chinese Subjects and HCV GT1b-Infected Chinese, South Korean and Taiwanese Patients.
    European journal of drug metabolism and pharmacokinetics, 2018
    Co-Authors: Jiuhong Zha, Bifeng Ding, Katia Alves, N Mobashery, Weihan Zhao, Haoyu Wang, Yan Luo, Rajeev M Menon
    Abstract:

    BACKGROUND/PURPOSE The 3 direct-acting antiviral (3D) regimen of ombitasvir/paritaprevir/ritonavir plus Dasabuvir has recently been approved in several Asian geographic regions for the treatment of hepatitis C virus (HCV) genotype (GT) 1 infection. The pharmacokinetics of the components of the 3D regimen with or without ribavirin were evaluated in healthy Chinese subjects and HCV GT1b-infected Chinese, South Korean, and Taiwanese patients, with or without cirrhosis, to determine how the drug exposures in Asian populations compare with historical data in Western populations. METHODS Participants received ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily plus Dasabuvir 250 mg twice daily for 14 days (healthy subjects, n = 36) or 12 weeks (HCV patients, n = 754). Patients with compensated cirrhosis also received ribavirin 1000 or 1200 mg divided twice daily, per the local label. Intensive or sparse pharmacokinetic sampling was performed for assessments of plasma drug concentrations. RESULTS The exposures [maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC)] of the components of the 3D regimen were comparable (

  • Pharmacokinetics of Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir in Healthy Chinese Subjects and HCV GT1b-Infected Chinese, South Korean and Taiwanese Patients.
    European Journal of Drug Metabolism and Pharmacokinetics, 2018
    Co-Authors: Bifeng Ding, Katia Alves, N Mobashery, Weihan Zhao, Chen Yu, Haoyu Wang, Rajeev M Menon
    Abstract:

    Background/Purpose The 3 direct-acting antiviral (3D) regimen of ombitasvir/paritaprevir/ritonavir plus Dasabuvir has recently been approved in several Asian geographic regions for the treatment of hepatitis C virus (HCV) genotype (GT) 1 infection. The pharmacokinetics of the components of the 3D regimen with or without ribavirin were evaluated in healthy Chinese subjects and HCV GT1b-infected Chinese, South Korean, and Taiwanese patients, with or without cirrhosis, to determine how the drug exposures in Asian populations compare with historical data in Western populations.

  • Population Pharmacokinetics of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin in Hepatitis C Virus-Infected Cirrhotic and Non-cirrhotic Patients: Analyses Across Nine Phase III Studies.
    Clinical Pharmacokinectics, 2018
    Co-Authors: Sathej Gopalakrishnan, Sven Mensing, Rajeev M Menon
    Abstract:

    Background The clinical development program of the direct-acting antiviral (DAA) combination therapy of paritaprevir (coadministered with ritonavir) and ombitasvir, with and without Dasabuvir (3-DAA [3D] and 2-DAA [2D] regimens, respectively) used in the treatment of chronic hepatitis C infection has generated a robust dataset across various dosing regimens and patient populations.

Daniel E. Cohen - One of the best experts on this subject based on the ideXlab platform.

  • Effects of chronic kidney disease stage 4, end-stage renal disease, or dialysis on the plasma concentrations of ombitasvir, paritaprevir, ritonavir, and Dasabuvir in patients with chronic HCV infection: pharmacokinetic analysis of the phase 3 RUBY-I
    European Journal of Clinical Pharmacology, 2018
    Co-Authors: Diana L. Shuster, Rajeev M Menon, Amit Khatri, Bifeng Ding, Eric Cohen, Melissa Jewett, Hong Li, Daniel E. Cohen
    Abstract:

    To characterize the pharmacokinetics of ombitasvir, paritaprevir, ritonavir, Dasabuvir, and ribavirin in hepatitis C virus (HCV)-infected patients with chronic kidney disease stage 4 (CKD4) or end-stage renal disease (ESRD), including those on dialysis, in the open-label phase 3 RUBY-I and RUBY-II studies. Patients (n = 18 CKD4, n = 68 ESRD) received ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily ± Dasabuvir 250 mg twice daily ± ribavirin 200 mg once daily for 12 or 24 weeks. Intensive pharmacokinetic samples were collected from ten patients; sparse samples were collected from all patients. Arterial and venous samples were collected from three patients during hemodialysis. Area under the plasma concentration-time curve (AUC) was estimated using noncompartmental analyses for intensive data, and steady-state trough concentrations (Ctrough) were obtained from the sparse data. Pharmacokinetic results from RUBY-I and RUBY-II were compared empirically to historical data. The AUC values of ombitasvir, paritaprevir, ritonavir, and Dasabuvir were comparable between CKD4 and ESRD patients and were within the range of values observed in historical studies; dialysis had no effect on drug exposures. Ribavirin was extracted during hemodialysis but had similar exposures on dialysis and non-dialysis days. Individual steady-state Ctrough values for each drug overlapped between CKD4 and ESRD patients, and values in both groups were similar to historical values. Plasma concentrations of ombitasvir, paritaprevir, ritonavir, and Dasabuvir were not altered by renal impairment or dialysis, suggesting these agents can be administered to HCV-infected CKD4 or ESRD patients, including those on dialysis, without dose adjustment. Clinicaltrials.gov identifiers: NCT02207088 (RUBY-I) and NCT02487199 (RUBY-II)

  • Effects of chronic kidney disease stage 4, end-stage renal disease, or dialysis on the plasma concentrations of ombitasvir, paritaprevir, ritonavir, and Dasabuvir in patients with chronic HCV infection: pharmacokinetic analysis of the phase 3 RUBY-I
    European journal of clinical pharmacology, 2018
    Co-Authors: Diana L. Shuster, Rajeev M Menon, Amit Khatri, Bifeng Ding, Eric Cohen, Melissa Jewett, Daniel E. Cohen, Jiuhong Zha
    Abstract:

    Purpose To characterize the pharmacokinetics of ombitasvir, paritaprevir, ritonavir, Dasabuvir, and ribavirin in hepatitis C virus (HCV)-infected patients with chronic kidney disease stage 4 (CKD4) or end-stage renal disease (ESRD), including those on dialysis, in the open-label phase 3 RUBY-I and RUBY-II studies. Methods Patients (n = 18 CKD4, n = 68 ESRD) received ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily ± Dasabuvir 250 mg twice daily ± ribavirin 200 mg once daily for 12 or 24 weeks. Intensive pharmacokinetic samples were collected from ten patients; sparse samples were collected from all patients. Arterial and venous samples were collected from three patients during hemodialysis. Area under the plasma concentration-time curve (AUC) was estimated using noncompartmental analyses for intensive data, and steady-state trough concentrations (Ctrough) were obtained from the sparse data. Pharmacokinetic results from RUBY-I and RUBY-II were compared empirically to historical data. Results The AUC values of ombitasvir, paritaprevir, ritonavir, and Dasabuvir were comparable between CKD4 and ESRD patients and were within the range of values observed in historical studies; dialysis had no effect on drug exposures. Ribavirin was extracted during hemodialysis but had similar exposures on dialysis and non-dialysis days. Individual steady-state Ctrough values for each drug overlapped between CKD4 and ESRD patients, and values in both groups were similar to historical values. Conclusion Plasma concentrations of ombitasvir, paritaprevir, ritonavir, and Dasabuvir were not altered by renal impairment or dialysis, suggesting these agents can be administered to HCV-infected CKD4 or ESRD patients, including those on dialysis, without dose adjustment. Trial registration Clinicaltrials.gov identifiers: NCT02207088 (RUBY-I) and NCT02487199 (RUBY-II).

  • effect of hepatitis c treatment with ombitasvir paritaprevir r Dasabuvir on renal cardiovascular and metabolic extrahepatic manifestations a post hoc analysis of phase 3 clinical trials
    Infectious Diseases and Therapy, 2017
    Co-Authors: Darshan A Mehta, Eric Cohen, Daniel E. Cohen, Mariem Charafeddine, Yuri Sanchez Gonzalez, Tram T Tran
    Abstract:

    Introduction We analyzed phase 3 trial data of ombitasvir/paritaprevir/ritonavir and Dasabuvir (3D) ± ribavirin (RBV) in genotype 1 chronic hepatitis C patients to investigate the impact of 3D ± RBV on renal, cardiovascular and metabolic extrahepatic manifestations (EHMs), including persistency 52 weeks post treatment and differential impact by EHM disease severity.

  • Effect of Hepatitis C Treatment with Ombitasvir/Paritaprevir/R + Dasabuvir on Renal, Cardiovascular and Metabolic Extrahepatic Manifestations: A Post-Hoc Analysis of Phase 3 Clinical Trials.
    Infectious Diseases and Therapy, 2017
    Co-Authors: Darshan A Mehta, Eric Cohen, Daniel E. Cohen, Mariem Charafeddine, Yuri Sanchez Gonzalez, Tram T Tran
    Abstract:

    Introduction We analyzed phase 3 trial data of ombitasvir/paritaprevir/ritonavir and Dasabuvir (3D) ± ribavirin (RBV) in genotype 1 chronic hepatitis C patients to investigate the impact of 3D ± RBV on renal, cardiovascular and metabolic extrahepatic manifestations (EHMs), including persistency 52 weeks post treatment and differential impact by EHM disease severity.

  • efficacy of direct acting antiviral combination for patients with hepatitis c virus genotype 1 infection and severe renal impairment or end stage renal disease
    Gastroenterology, 2016
    Co-Authors: Paul J Pockros, Eric Cohen, Daniel E. Cohen, Parvez S Mantry, Nancy S Shulman, Mark S Sulkowski, David Bernstein, Rajender K Reddy, Michael J. Bennett, Deli Wang
    Abstract:

    Background & Aims Although hepatitis C virus (HCV) infection is common in patients with end-stage renal disease, highly efficacious, well-tolerated, direct-acting antiviral regimens have not been extensively studied in this population. We investigated the safety and efficacy of ombitasvir co-formulated with paritaprevir and ritonavir, administered with Dasabuvir (with or without ribavirin) in a prospective study of patients with stage 4 or 5 chronic kidney disease (CKD). Methods We performed a single-arm, multicenter study of treatment-naive adults with HCV genotype 1 infection, without cirrhosis and with CKD stage 4 (estimated glomerular filtration rate, 15–30 mL/min/1.73 m 2 ) or stage 5 (estimated glomerular filtration rate, 2 or requiring hemodialysis). Twenty patients were given ombitasvir co-formulated with paritaprevir and ritonavir, administered with Dasabuvir for 12 weeks. Patients with HCV genotype 1a infections also received ribavirin (n = 13), whereas those with genotype 1b infection did not (n = 7). The primary end point was sustained virologic response (serum HCV RNA Results All 20 patients completed 12 weeks of treatment. Eighteen of the 20 patients achieved SVR12 (90%; 95% confidence interval: 69.9–97.2). One patient death after the end of the treatment (unrelated to the treatment) and 1 relapse accounted for the 2 non-SVRs. Adverse events were primarily mild or moderate, and no patient discontinued treatment due to an AE. Four patients experienced serious AEs; all were considered unrelated to treatment. Ribavirin therapy was interrupted in 9 patients due to anemia; 4 received erythropoietin. No blood transfusions were performed. Conclusions In a clinical trial, the combination of ombitasvir, paritaprevir, and ritonavir, administered with Dasabuvir, led to an SVR12 in 90% of patients with HCV genotype 1 infection and stage 4 or 5 CKD. The regimen is well tolerated, though RBV use may require a reduction or interruption to manage anemia. ClinicalTrials.gov ID NCT02207088.

Mitchell L. Shiffman - One of the best experts on this subject based on the ideXlab platform.

  • safety and efficacy of ombitasvir paritaprevir ritonavir plus Dasabuvir with or without ribavirin in hcv infected patients taking concomitant acid reducing agents
    The American Journal of Gastroenterology, 2016
    Co-Authors: Mitchell L. Shiffman, Ramon Planas Vila, Marcos Pedrosa, Jonathan Moller, Vinod K Rustgi, Tarik Asselah, Xavier Forns, Michael J. Bennett, Nancy Reau
    Abstract:

    Safety and Efficacy of Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir With or Without Ribavirin in HCV-Infected Patients Taking Concomitant Acid-Reducing Agents

  • Safety and Efficacy of Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir With or Without Ribavirin in HCV-Infected Patients Taking Concomitant Acid-Reducing Agents.
    The American Journal of Gastroenterology, 2016
    Co-Authors: Mitchell L. Shiffman, Ramon Planas Vila, Marcos Pedrosa, Jonathan Moller, Vinod K Rustgi, Tarik Asselah, Xavier Forns, Michael J. Bennett, Nancy Reau
    Abstract:

    Safety and Efficacy of Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir With or Without Ribavirin in HCV-Infected Patients Taking Concomitant Acid-Reducing Agents

  • ombitasvir paritaprevir r Dasabuvir and ribavirin for cirrhotic hcv patients with thrombocytopaenia and hypoalbuminaemia
    Liver International, 2015
    Co-Authors: Xavier Forns, Fred Poordad, Marcos Pedrosa, Marina Berenguer, Sandra Lovell, Heiner Wedemeyer, Peter Ferenci, Mitchell L. Shiffman, Michael W. Fried, Roger Trinh
    Abstract:

    Background & Aims Thrombocytopaenia and hypoalbuminaemia are surrogate markers for portal hypertension and hepatic synthetic dysfunction respectively. Patients infected with hepatitis C virus (HCV) with these surrogates have reduced likelihood of sustained virologic response and increased risk for hepatic decompensation or death when treated with peginterferon/ribavirin plus either telaprevir or boceprevir. Methods We conducted a post-hoc analysis of the TURQUOISE-II clinical trial in patients with cirrhosis to examine the impact of these surrogates on efficacy and safety of ombitasvir/paritaprevir/ritonavir and Dasabuvir with ribavirin. Results Of 380 genotype 1-infected patients in TURQUOISE-II, 104 had either a platelet count <100 × 109/L or albumin <3.5 g/dl. Sustained virologic response rates were 89 and 97% in patients with thrombocytopaenia, and 84 and 89% in patients with hypoalbuminaemia after 12 and 24 weeks of ombitasvir/paritaprevir/ritonavir and Dasabuvir with ribavirin respectively. These rates were similar to those observed in the overall study population (92 and 97% for 12 and 24 weeks). HCV genotype 1a-infected patients with thrombocytopaenia or hypoalbuminaemia had higher response rates when treated for 24 weeks, whereas only 1 of 35 genotype 1b patients did not achieve a sustained virologic response. Adverse event rates and discontinuations because of adverse events were low. Conclusions The findings of these analyses support the use of ombitasvir/paritaprevir/ritonavir and Dasabuvir with ribavirin in these subpopulations with cirrhosis. Genotype 1a-infected patients with indicators of portal hypertension may benefit from a 24-week treatment duration.

  • Ombitasvir/paritaprevir/r, Dasabuvir and ribavirin for cirrhotic HCV patients with thrombocytopaenia and hypoalbuminaemia.
    Liver International, 2015
    Co-Authors: Xavier Forns, Fred Poordad, Marcos Pedrosa, Marina Berenguer, Sandra Lovell, Heiner Wedemeyer, Peter Ferenci, Mitchell L. Shiffman, Michael W. Fried, Roger Trinh
    Abstract:

    Background & Aims Thrombocytopaenia and hypoalbuminaemia are surrogate markers for portal hypertension and hepatic synthetic dysfunction respectively. Patients infected with hepatitis C virus (HCV) with these surrogates have reduced likelihood of sustained virologic response and increased risk for hepatic decompensation or death when treated with peginterferon/ribavirin plus either telaprevir or boceprevir. Methods We conducted a post-hoc analysis of the TURQUOISE-II clinical trial in patients with cirrhosis to examine the impact of these surrogates on efficacy and safety of ombitasvir/paritaprevir/ritonavir and Dasabuvir with ribavirin. Results Of 380 genotype 1-infected patients in TURQUOISE-II, 104 had either a platelet count

  • abt 450 r ombitasvir and Dasabuvir with ribavirin for hepatitis c with cirrhosis
    The New England Journal of Medicine, 2014
    Co-Authors: Fred Poordad, Roger Trinh, Kris V Kowdley, Heiner Wedemeyer, Christophe Hezode, Mitchell L. Shiffman, S Zeuzem, K Agarwal, T Berg, Eric M Yoshida
    Abstract:

    Background Interferon-containing regimens for the treatment of hepatitis C virus (HCV) infection are associated with increased toxic effects in patients who also have cirrhosis. We evaluated the interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r), the NS5A inhibitor ombitasvir (ABT-267), the nonnucleoside polymerase inhibitor Dasabuvir (ABT-333), and ribavirin in an open-label phase 3 trial involving previously untreated and previously treated adults with HCV genotype 1 infection and compensated cirrhosis. Methods We randomly assigned 380 patients with Child–Pugh class A cirrhosis to receive either 12 or 24 weeks of treatment with ABT-450/r–ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), Dasabuvir (250 mg twice daily), and ribavirin administered according to body weight. The primary efficacy end point was a sustained virologic response 12 weeks after the end of treatment. The rate of sustained virologic response in ...

Amit Khatri - One of the best experts on this subject based on the ideXlab platform.

  • Effects of chronic kidney disease stage 4, end-stage renal disease, or dialysis on the plasma concentrations of ombitasvir, paritaprevir, ritonavir, and Dasabuvir in patients with chronic HCV infection: pharmacokinetic analysis of the phase 3 RUBY-I
    European Journal of Clinical Pharmacology, 2018
    Co-Authors: Diana L. Shuster, Rajeev M Menon, Amit Khatri, Bifeng Ding, Eric Cohen, Melissa Jewett, Hong Li, Daniel E. Cohen
    Abstract:

    To characterize the pharmacokinetics of ombitasvir, paritaprevir, ritonavir, Dasabuvir, and ribavirin in hepatitis C virus (HCV)-infected patients with chronic kidney disease stage 4 (CKD4) or end-stage renal disease (ESRD), including those on dialysis, in the open-label phase 3 RUBY-I and RUBY-II studies. Patients (n = 18 CKD4, n = 68 ESRD) received ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily ± Dasabuvir 250 mg twice daily ± ribavirin 200 mg once daily for 12 or 24 weeks. Intensive pharmacokinetic samples were collected from ten patients; sparse samples were collected from all patients. Arterial and venous samples were collected from three patients during hemodialysis. Area under the plasma concentration-time curve (AUC) was estimated using noncompartmental analyses for intensive data, and steady-state trough concentrations (Ctrough) were obtained from the sparse data. Pharmacokinetic results from RUBY-I and RUBY-II were compared empirically to historical data. The AUC values of ombitasvir, paritaprevir, ritonavir, and Dasabuvir were comparable between CKD4 and ESRD patients and were within the range of values observed in historical studies; dialysis had no effect on drug exposures. Ribavirin was extracted during hemodialysis but had similar exposures on dialysis and non-dialysis days. Individual steady-state Ctrough values for each drug overlapped between CKD4 and ESRD patients, and values in both groups were similar to historical values. Plasma concentrations of ombitasvir, paritaprevir, ritonavir, and Dasabuvir were not altered by renal impairment or dialysis, suggesting these agents can be administered to HCV-infected CKD4 or ESRD patients, including those on dialysis, without dose adjustment. Clinicaltrials.gov identifiers: NCT02207088 (RUBY-I) and NCT02487199 (RUBY-II)

  • Effects of chronic kidney disease stage 4, end-stage renal disease, or dialysis on the plasma concentrations of ombitasvir, paritaprevir, ritonavir, and Dasabuvir in patients with chronic HCV infection: pharmacokinetic analysis of the phase 3 RUBY-I
    European journal of clinical pharmacology, 2018
    Co-Authors: Diana L. Shuster, Rajeev M Menon, Amit Khatri, Bifeng Ding, Eric Cohen, Melissa Jewett, Daniel E. Cohen, Jiuhong Zha
    Abstract:

    Purpose To characterize the pharmacokinetics of ombitasvir, paritaprevir, ritonavir, Dasabuvir, and ribavirin in hepatitis C virus (HCV)-infected patients with chronic kidney disease stage 4 (CKD4) or end-stage renal disease (ESRD), including those on dialysis, in the open-label phase 3 RUBY-I and RUBY-II studies. Methods Patients (n = 18 CKD4, n = 68 ESRD) received ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily ± Dasabuvir 250 mg twice daily ± ribavirin 200 mg once daily for 12 or 24 weeks. Intensive pharmacokinetic samples were collected from ten patients; sparse samples were collected from all patients. Arterial and venous samples were collected from three patients during hemodialysis. Area under the plasma concentration-time curve (AUC) was estimated using noncompartmental analyses for intensive data, and steady-state trough concentrations (Ctrough) were obtained from the sparse data. Pharmacokinetic results from RUBY-I and RUBY-II were compared empirically to historical data. Results The AUC values of ombitasvir, paritaprevir, ritonavir, and Dasabuvir were comparable between CKD4 and ESRD patients and were within the range of values observed in historical studies; dialysis had no effect on drug exposures. Ribavirin was extracted during hemodialysis but had similar exposures on dialysis and non-dialysis days. Individual steady-state Ctrough values for each drug overlapped between CKD4 and ESRD patients, and values in both groups were similar to historical values. Conclusion Plasma concentrations of ombitasvir, paritaprevir, ritonavir, and Dasabuvir were not altered by renal impairment or dialysis, suggesting these agents can be administered to HCV-infected CKD4 or ESRD patients, including those on dialysis, without dose adjustment. Trial registration Clinicaltrials.gov identifiers: NCT02207088 (RUBY-I) and NCT02487199 (RUBY-II).

  • Clinical Pharmacokinetics of Dasabuvir
    Clinical Pharmacokinetics, 2017
    Co-Authors: Jennifer R King, Amit Khatri, Sandeep Dutta, Rajeev M Menon
    Abstract:

    Dasabuvir is a nonstructural (NS) 5B non-nucleoside inhibitor of the hepatitis C virus (HCV) used in combination with ombitasvir/paritaprevir/ritonavir for the treatment of chronic HCV infection. It is primarily metabolized by cytochrome P450 (CYP) 2C8, with a minor contribution from CYP3A. Biotransformation of Dasabuvir forms the M1 metabolite, which retains antiviral activity. Dasabuvir exhibits linear pharmacokinetics with a terminal half-life of approximately 5–8 h, allowing for twice-daily dosing. The M1 metabolite of Dasabuvir is the major metabolite in plasma and has a half-life similar to that of Dasabuvir. Dasabuvir exposures in Asian subjects are comparable with Caucasian subjects. The pharmacokinetic characteristics of Dasabuvir are similar between healthy subjects and HCV-infected patients, and are not appreciably altered by mild, moderate, or severe renal impairment or dialysis. Dasabuvir pharmacokinetic parameters were not significantly altered in subjects with mild or moderate hepatic impairment; however, exposures were significantly increased in subjects with severe hepatic impairment. Dasabuvir should be administered with food to maximize absorption. Coadministration of Dasabuvir with a strong CYP2C8 inhibitor increased Dasabuvir exposures by greater than tenfold, whereas coadministration with strong CYP3A inhibitors increased Dasabuvir exposures by less than 50%. Furthermore, coadministration of Dasabuvir with a CYP3A inducer decreased Dasabuvir exposures by 55–70%. Coadministration of Dasabuvir with strong CYP2C8 inhibitors or strong CYP3A/CYP2C8 inducers is contraindicated. Results from several drug interaction studies demonstrated that Dasabuvir in combination with ombitasvir/paritaprevir/ritonavir can be coadministered with most comedications that are commonly prescribed in HCV-infected patients.

  • pharmacokinetics and tolerability of anti hepatitis c virus treatment with ombitasvir paritaprevir ritonavir with or without Dasabuvir in subjects with renal impairment
    Clinical Pharmacokinectics, 2017
    Co-Authors: Amit Khatri, Sandeep Dutta, Thomas Marbury, Lino Rodrigues, Richard A Preston, Walid M Awni, Haoyu Wang, Rajeev M Menon
    Abstract:

    Background The direct-acting antiviral agent (DAA) combination of ombitasvir and paritaprevir (administered with ritonavir) with (3D regimen) or without (2D regimen) Dasabuvir has shown very high efficacy rates in the treatment of chronic hepatitis C virus (HCV) infection. Renal impairment, a common comorbidity in patients with chronic HCV infection, can influence the pharmacokinetics of antiviral agents and hence their efficacy and safety profiles.

  • Exposure-Efficacy Analyses of Ombitasvir, Paritaprevir/Ritonavir with Dasabuvir ± Ribavirin in HCV Genotype 1-Infected Patients
    Clinical Drug Investigation, 2016
    Co-Authors: Amit Khatri, Thomas Podsadecki, Sven Mensing, Walid M Awni, Rajeev Menon, Sandeep Dutta
    Abstract:

    Background and Objectives The three-direct-acting antiviral (DAA) combination regimen of ombitasvir, paritaprevir (coadministered with ritonavir [paritaprevir/ritonavir], and Dasabuvir (the 3D regimen) ± ribavirin for treatment of HCV genotype 1-infected patients demonstrated efficacy and safety in Phase II and Phase III clinical trials. The relationships between the steady-state exposure (area under the concentration-time curve at steady state and trough concentration at steady state) of the three DAAs and ribavirin with sustained virologic response at 12 weeks after treatment (SVR_12) following administration of the 3D regimen in six Phase II/III studies were examined. Methods HCV non-cirrhotic genotype 1-infected adult male and female patients ( N  = 1690) enrolled in the one Phase II study or one of the five Phase III studies were included for graphical analysis. HCV subgenotype 1a-infected patients who received the 3D regimen with ribavirin (approved regimen for that patient population) ( N  = 615) from the same studies were included in the multivariate logistic regression exposure-response analysis. Results Graphical analysis suggested a shallow trend between exposure and % SVR_12 for paritaprevir, ombitasvir, and ribavirin exposure but not for Dasabuvir exposure. After adjusting for covariate effects, the exposure-response logistic-regression analysis indicated that ombitasvir exposure was the single significant predictor, demonstrating a 1 % change in SVR_12 with up to 25 % change in ombitasvir exposure at steady state. Conclusions The results of these analyses indicate that the doses selected for the 3D regimen were optimal, achieving high SVR_12 rates across the range of exposures observed in the Phase III studies.

Nancy Reau - One of the best experts on this subject based on the ideXlab platform.

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