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Rajeev M Menon - One of the best experts on this subject based on the ideXlab platform.
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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, 2018Co-Authors: Diana L. Shuster, Rajeev M Menon, Amit Khatri, Bifeng Ding, Eric Cohen, Melissa Jewett, Daniel E. Cohen, Jiuhong ZhaAbstract: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).
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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, 2018Co-Authors: Diana L. Shuster, Rajeev M Menon, Amit Khatri, Bifeng Ding, Eric Cohen, Melissa Jewett, Hong Li, Daniel E. CohenAbstract: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)
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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, 2018Co-Authors: Jiuhong Zha, Bifeng Ding, Katia Alves, N Mobashery, Haoyu Wang, Yan Luo, Weihan Zhao, Rajeev M MenonAbstract: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 (
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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, 2018Co-Authors: Sathej Gopalakrishnan, Sven Mensing, Rajeev M MenonAbstract: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.
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Clinical Pharmacokinetics of Ombitasvir
Clinical Pharmacokinetics, 2017Co-Authors: Prajakta S Badri, Sandeep Dutta, Diana L. Shuster, Rajeev M MenonAbstract:Ombitasvir is a potent, nonstructural protein 5A inhibitor of the hepatitis C virus (HCV) that is used in combination with other direct-acting antivirals for the treatment of chronic HCV infection. Ombitasvir is predominantly metabolized by amide hydrolysis followed by oxidative metabolism and is a substrate of P-glycoprotein. Ombitasvir displays linear pharmacokinetics with minimal accumulation and is eliminated via metabolism and biliary excretion. A negligible amount of unchanged drug is excreted in urine. Exposures are comparable across Chinese, Japanese, and non-Asian subjects. The pharmacokinetic characteristics of Ombitasvir are similar in healthy subjects and HCV-infected patients, and are not appreciably altered by hepatic or renal impairment. Results from several drug interaction studies demonstrated that Ombitasvir has a low potential for drug interactions.
Daniel E. Cohen - One of the best experts on this subject based on the ideXlab platform.
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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, 2018Co-Authors: Diana L. Shuster, Rajeev M Menon, Amit Khatri, Bifeng Ding, Eric Cohen, Melissa Jewett, Daniel E. Cohen, Jiuhong ZhaAbstract: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).
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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, 2018Co-Authors: Diana L. Shuster, Rajeev M Menon, Amit Khatri, Bifeng Ding, Eric Cohen, Melissa Jewett, Hong Li, Daniel E. CohenAbstract: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)
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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, 2017Co-Authors: Darshan A Mehta, Eric Cohen, Daniel E. Cohen, Mariem Charafeddine, Yuri Sanchez Gonzalez, Tram T TranAbstract: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.
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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, 2017Co-Authors: Darshan A Mehta, Eric Cohen, Daniel E. Cohen, Mariem Charafeddine, Yuri Sanchez Gonzalez, Tram T TranAbstract: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.
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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, 2016Co-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 WangAbstract: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.
Amit Khatri - One of the best experts on this subject based on the ideXlab platform.
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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, 2018Co-Authors: Diana L. Shuster, Rajeev M Menon, Amit Khatri, Bifeng Ding, Eric Cohen, Melissa Jewett, Hong Li, Daniel E. CohenAbstract: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)
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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, 2018Co-Authors: Diana L. Shuster, Rajeev M Menon, Amit Khatri, Bifeng Ding, Eric Cohen, Melissa Jewett, Daniel E. Cohen, Jiuhong ZhaAbstract: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).
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pharmacokinetics and tolerability of anti hepatitis c virus treatment with Ombitasvir paritaprevir ritonavir with or without dasabuvir in subjects with renal impairment
Clinical Pharmacokinectics, 2017Co-Authors: Amit Khatri, Sandeep Dutta, Thomas Marbury, Lino Rodrigues, Richard A Preston, Walid M Awni, Haoyu Wang, Rajeev M MenonAbstract: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.
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Population Pharmacokinetics of Paritaprevir, Ombitasvir, and Ritonavir in Japanese Patients with Hepatitis C Virus Genotype 1b Infection
Clinical Pharmacokinetics, 2017Co-Authors: Sathej M. Gopalakrishnan, Amit Khatri, Akshanth R. Polepally, Sven Mensing, Rajeev M MenonAbstract:Background and Objective Hepatitis C virus (HCV) infection is of considerable clinical concern in Japan. We modeled the population pharmacokinetics of an oral interferon-free, direct-acting antiviral agent (DAA) regimen (i.e., the 2D regimen) recently approved for the treatment of chronic HCV genotype 1 infection as a new option for affected Japanese patients. Methods Using data from a phase III clinical trial (GIFT-I) that enrolled Japanese patients with HCV genotype 1b infection, population pharmacokinetic models were developed for the drugs that comprise the 2D regimen: paritaprevir, Ombitasvir, and ritonavir. Demographic and clinical covariates with potential to influence 2D pharmacokinetics were evaluated for their effects on drug exposures. Proposed models were assessed using goodness-of-fit plots, visual predictive checks, and bootstrap evaluations. Results One-compartment models with first-order absorption and elimination adequately described the population pharmacokinetics of paritaprevir, Ombitasvir, and ritonavir. On average, patients with cirrhosis had approximately 95–145 % higher, 19–24 % lower, and 58–68 % higher exposures of paritaprevir, Ombitasvir, and ritonavir, respectively. Female patients had 58–81 % higher Ombitasvir exposures, whereas patients with mild renal impairment (creatinine clearance 75 mL/min) had 9–14 % higher Ombitasvir exposures than did patients with normal renal function (creatinine clearance 105 mL/min). The DAA exposure values were comparable between responders and non-responders. Conclusion Population pharmacokinetic modeling did not reveal any patient-related or clinical parameters that would require dose adjustment of the 2D regimen when used for the treatment of HCV genotype 1b infection in Japanese patients.
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Exposure-Efficacy Analyses of Ombitasvir, Paritaprevir/Ritonavir with Dasabuvir ± Ribavirin in HCV Genotype 1-Infected Patients
Clinical Drug Investigation, 2016Co-Authors: Amit Khatri, Thomas Podsadecki, Sven Mensing, Walid M Awni, Rajeev Menon, Sandeep DuttaAbstract: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.
Sandeep Dutta - One of the best experts on this subject based on the ideXlab platform.
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Clinical Pharmacokinetics of Ombitasvir
Clinical Pharmacokinetics, 2017Co-Authors: Prajakta S Badri, Sandeep Dutta, Diana L. Shuster, Rajeev M MenonAbstract:Ombitasvir is a potent, nonstructural protein 5A inhibitor of the hepatitis C virus (HCV) that is used in combination with other direct-acting antivirals for the treatment of chronic HCV infection. Ombitasvir is predominantly metabolized by amide hydrolysis followed by oxidative metabolism and is a substrate of P-glycoprotein. Ombitasvir displays linear pharmacokinetics with minimal accumulation and is eliminated via metabolism and biliary excretion. A negligible amount of unchanged drug is excreted in urine. Exposures are comparable across Chinese, Japanese, and non-Asian subjects. The pharmacokinetic characteristics of Ombitasvir are similar in healthy subjects and HCV-infected patients, and are not appreciably altered by hepatic or renal impairment. Results from several drug interaction studies demonstrated that Ombitasvir has a low potential for drug interactions.
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Exposure-Safety Response Relationship for Ombitasvir, Paritaprevir/Ritonavir, Dasabuvir, and Ribavirin in Patients with Chronic Hepatitis C Virus Genotype 1 Infection: Analysis of Data from Five Phase II and Six Phase III Studies.
Clinical Drug Investigation, 2017Co-Authors: Rajeev M Menon, Thomas Podsadecki, Nancy S Shulman, Barbara Dasilva-tillmann, Walid M Awni, Sandeep DuttaAbstract:Background and Objectives All-oral direct-acting antiviral regimens that include combinations of Ombitasvir, paritaprevir, ritonavir, and dasabuvir with or without ribavirin were evaluated in hepatitis C virus-infected patients in phase II/III clinical studies. The objective of these analyses was to quantify the relationship between exposures of the components of the regimen and laboratory values and to determine covariates that could influence the relationship.
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pharmacokinetics and tolerability of anti hepatitis c virus treatment with Ombitasvir paritaprevir ritonavir with or without dasabuvir in subjects with renal impairment
Clinical Pharmacokinectics, 2017Co-Authors: Amit Khatri, Sandeep Dutta, Thomas Marbury, Lino Rodrigues, Richard A Preston, Walid M Awni, Haoyu Wang, Rajeev M MenonAbstract: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.
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Exposure-Efficacy Analyses of Ombitasvir, Paritaprevir/Ritonavir with Dasabuvir ± Ribavirin in HCV Genotype 1-Infected Patients
Clinical Drug Investigation, 2016Co-Authors: Amit Khatri, Thomas Podsadecki, Sven Mensing, Walid M Awni, Rajeev Menon, Sandeep DuttaAbstract: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.
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drug drug interaction of omeprazole with the hcv direct acting antiviral agents paritaprevir ritonavir and Ombitasvir with and without dasabuvir
Clinical pharmacology in drug development, 2016Co-Authors: Akshanth R. Polepally, Thomas Podsadecki, Sandeep Dutta, Beibei Hu, Walid M Awni, Rajeev M MenonAbstract: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.
Michael J. Bennett - One of the best experts on this subject based on the ideXlab platform.
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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, 2016Co-Authors: Mitchell L. Shiffman, Ramon Planas Vila, Marcos Pedrosa, Jonathan Moller, Vinod K Rustgi, Tarik Asselah, Xavier Forns, Michael J. Bennett, Nancy ReauAbstract:Safety and Efficacy of Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir With or Without Ribavirin in HCV-Infected Patients Taking Concomitant Acid-Reducing Agents
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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, 2016Co-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 WangAbstract: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.
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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, 2016Co-Authors: Mitchell L. Shiffman, Ramon Planas Vila, Marcos Pedrosa, Jonathan Moller, Vinod K Rustgi, Tarik Asselah, Xavier Forns, Michael J. Bennett, Nancy ReauAbstract:Safety and Efficacy of Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir With or Without Ribavirin in HCV-Infected Patients Taking Concomitant Acid-Reducing Agents
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exploratory trial of Ombitasvir and abt 450 r with or without ribavirin for hcv genotype 1 2 and 3 infection
Journal of Infection, 2015Co-Authors: Eric Lawitz, Lino Rodrigues, Prajakta S Badri, Fred Poordad, Michael J. Bennett, Andrew L Campbell, Greg Sullivan, Mudra Kapoor, Maribel Rodrigueztorres, Tami PilotmatiasAbstract:Summary Objectives To examine the safety and efficacy of Ombitasvir and ABT-450 with ritonavir (ABT-450/r) ± ribavirin (RBV) in treatment-naive, non-cirrhotic adults with chronic HCV genotype 1–3 infection. Methods Patients in this open-label, exploratory, phase 2, multicenter study received Ombitasvir (25 mg QD) and ABT-450/r (200/100 mg QD) ± RBV for 12 weeks. Primary efficacy endpoint was HCV RNA 12 ) was a secondary endpoint. Results Sixty-one patients were enrolled. Among genotype 1-, 2-, and 3-infected patients, respectively, HCV RNA was 12 was achieved by 10 (100%), 8 (80%), and 5 (50%) receiving the RBV-containing regimen, and 6 (60%), 6 (60%), and 1 (9%) receiving the RBV-free regimen. The most common adverse events were fatigue, nausea, and headache. One patient discontinued due to an adverse event. Conclusions In this study, Ombitasvir and ABT-450/r ± RBV regimens were generally well-tolerated. Sustained virologic response was achieved in most patients with HCV genotype 1 or 2 infection, but low SVR rates were observed in HCV genotype 3-infected patients.
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Exploratory trial of Ombitasvir and ABT-450/r with or without ribavirin for HCV genotype 1, 2, and 3 infection
The Journal of infection, 2014Co-Authors: Eric Lawitz, Prajakta S Badri, Fred Poordad, Michael J. Bennett, Greg Sullivan, Maribel Rodriguez-torres, Mudra Kapoor, Campbell Andrew L, Lino RodriguesAbstract:Summary Objectives To examine the safety and efficacy of Ombitasvir and ABT-450 with ritonavir (ABT-450/r) ± ribavirin (RBV) in treatment-naive, non-cirrhotic adults with chronic HCV genotype 1–3 infection. Methods Patients in this open-label, exploratory, phase 2, multicenter study received Ombitasvir (25 mg QD) and ABT-450/r (200/100 mg QD) ± RBV for 12 weeks. Primary efficacy endpoint was HCV RNA 12 ) was a secondary endpoint. Results Sixty-one patients were enrolled. Among genotype 1-, 2-, and 3-infected patients, respectively, HCV RNA was 12 was achieved by 10 (100%), 8 (80%), and 5 (50%) receiving the RBV-containing regimen, and 6 (60%), 6 (60%), and 1 (9%) receiving the RBV-free regimen. The most common adverse events were fatigue, nausea, and headache. One patient discontinued due to an adverse event. Conclusions In this study, Ombitasvir and ABT-450/r ± RBV regimens were generally well-tolerated. Sustained virologic response was achieved in most patients with HCV genotype 1 or 2 infection, but low SVR rates were observed in HCV genotype 3-infected patients.
