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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, Hong Li, Eric Cohen, Melissa Jewett, 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: Bifeng Ding, Katia Alves, N Mobashery, Haoyu Wang, Weihan Zhao, Chen Yu, 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.

  • Clinical Pharmacokinetics of Paritaprevir
    Clinical Pharmacokinetics, 2017
    Co-Authors: Rajeev M Menon, Walid M Awni, Akshanth R. Polepally, Amit Khatri, Sandeep Dutta
    Abstract:

    Paritaprevir is a potent hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor that is used in combination with other direct-acting antivirals (DAAs) for the treatment of chronic HCV infection. Paritaprevir is primarily metabolized by cytochrome P450 (CYP) 3A4 and is administered with a low dose of ritonavir to achieve drug concentrations suitable for once-daily dosing. Coadministration of Paritaprevir with ritonavir increases the half-life of single-dose Paritaprevir from approximately 3 h to 5–8 h, doubles the time to maximum plasma concentration ( T _max) from 2.3 to 4.7 h, and increases exposures 30-fold for maximum observed plasma concentration ( C _max), 50-fold for area under the plasma concentration–time curve (AUC), and >300-fold for trough concentration ( C _24). Paritaprevir displays highly variable, nonlinear pharmacokinetics, with C _max and AUC increasing in a greater than dose proportional manner when administered with or without ritonavir. In the presence of ritonavir, Paritaprevir is excreted mostly unchanged in feces via biliary excretion. Paritaprevir exposures are higher in Japanese subjects compared with Caucasian subjects; however, no dose adjustment is needed for Japanese patients as the higher exposures are safe and well tolerated. The pharmacokinetic characteristics of Paritaprevir are similar between healthy subjects and HCV-infected patients, and are not appreciably altered by mild or moderate hepatic impairment or mild, moderate, or severe renal impairment, including those on dialysis. Paritaprevir exposures are increased in patients with severe hepatic impairment. Although the presence of a low dose of ritonavir in Paritaprevir-containing regimens increases the likelihood of drug–drug interactions, results from several drug interaction studies demonstrated that Paritaprevir-containing regimens can be coadministered with many comedications that are commonly prescribed in HCV-infected patients.

  • 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.

Sandeep Dutta - One of the best experts on this subject based on the ideXlab platform.

  • Clinical Pharmacokinetics of Paritaprevir
    Clinical Pharmacokinetics, 2017
    Co-Authors: Rajeev M Menon, Walid M Awni, Akshanth R. Polepally, Amit Khatri, Sandeep Dutta
    Abstract:

    Paritaprevir is a potent hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor that is used in combination with other direct-acting antivirals (DAAs) for the treatment of chronic HCV infection. Paritaprevir is primarily metabolized by cytochrome P450 (CYP) 3A4 and is administered with a low dose of ritonavir to achieve drug concentrations suitable for once-daily dosing. Coadministration of Paritaprevir with ritonavir increases the half-life of single-dose Paritaprevir from approximately 3 h to 5–8 h, doubles the time to maximum plasma concentration ( T _max) from 2.3 to 4.7 h, and increases exposures 30-fold for maximum observed plasma concentration ( C _max), 50-fold for area under the plasma concentration–time curve (AUC), and >300-fold for trough concentration ( C _24). Paritaprevir displays highly variable, nonlinear pharmacokinetics, with C _max and AUC increasing in a greater than dose proportional manner when administered with or without ritonavir. In the presence of ritonavir, Paritaprevir is excreted mostly unchanged in feces via biliary excretion. Paritaprevir exposures are higher in Japanese subjects compared with Caucasian subjects; however, no dose adjustment is needed for Japanese patients as the higher exposures are safe and well tolerated. The pharmacokinetic characteristics of Paritaprevir are similar between healthy subjects and HCV-infected patients, and are not appreciably altered by mild or moderate hepatic impairment or mild, moderate, or severe renal impairment, including those on dialysis. Paritaprevir exposures are increased in patients with severe hepatic impairment. Although the presence of a low dose of ritonavir in Paritaprevir-containing regimens increases the likelihood of drug–drug interactions, results from several drug interaction studies demonstrated that Paritaprevir-containing regimens can be coadministered with many comedications that are commonly prescribed in HCV-infected patients.

  • 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.

  • 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, 2017
    Co-Authors: Rajeev M Menon, Thomas Podsadecki, Walid M Awni, Nancy S Shulman, Barbara Dasilva-tillmann, Sandeep Dutta
    Abstract:

    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.

  • 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, Walid M Awni, Thomas Marbury, Lino Rodrigues, Richard A Preston, 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.

  • Effect of co-medications on Paritaprevir, ritonavir, ombitasvir, dasabuvir and ribavirin pharmacokinetics: analysis of data from seven Phase II/III trials.
    Antiviral Therapy, 2016
    Co-Authors: Akshanth R. Polepally, Thomas Podsadecki, Sandeep Dutta, Walid M Awni, Sven Mensing, Lino Rodrigues, Prajakta S Badri, Apurvasena Parikh, Barbara Da Silva-tillmann, Rajeev M Menon
    Abstract:

    BACKGROUND: The three drug direct-acting antiviral regimen (3D regimen) of ombitasvir, Paritaprevir/ritonavir and dasabuvir, with and without ribavirin, was evaluated in one Phase II trial and six Phase III trials in over 2,300 HCV genotype-1-infected patients. Patients continued taking their protocol-permitted co-medications while receiving the 3D ± ribavirin regimen. The effects of the co-medications on exposures of the 3D regimen and ribavirin were examined. METHODS: Population pharmacokinetic model-predicted steady-state area under the curve (AUC24,ss) values were evaluated in the presence/absence of the co-medications. Interactions resulting in a greater than 50% reduction or 100% increase in an AUC24,ss value were examined as covariates for an effect on apparent clearance (CL/F). RESULTS: More than 1,200 co-medications belonging to 15 drug classes and/or 19 enzyme and transporter inhibitor and/or inducer categories were used concomitantly with the 3D regimen in the trials. Approximately 1,500 patients (65%) in Phase III trials received two or more co-medications from multiple drug classes or categories. No co-medication class/category decreased or increased ombitasvir, dasabuvir, ritonavir or ribavirin AUC24,ss by more than half or twofold, respectively. Opioids, antipsychotics, anti-epileptics, antidiabetics and non-ethinyl estradiol-containing hormone replacement therapies appeared to have an effect (AUC24,ss ratio ≤0.5 or ≥2.0) on Paritaprevir exposures. However, when these classes were included in the Paritaprevir population pharmacokinetic model, only opioids and antidiabetics had a statistically significant effect on CL/F, but with no clinically meaningful increase in exposures (≤55%). CONCLUSIONS: No dose adjustment is necessary for the 3D ± ribavirin regimen when used with the co-medications included in this analysis as there were no clinically meaningful effects on exposures of the DAAs.

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, Hong Li, Eric Cohen, Melissa Jewett, 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)

  • Clinical Pharmacokinetics of Paritaprevir
    Clinical Pharmacokinetics, 2017
    Co-Authors: Rajeev M Menon, Walid M Awni, Akshanth R. Polepally, Amit Khatri, Sandeep Dutta
    Abstract:

    Paritaprevir is a potent hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor that is used in combination with other direct-acting antivirals (DAAs) for the treatment of chronic HCV infection. Paritaprevir is primarily metabolized by cytochrome P450 (CYP) 3A4 and is administered with a low dose of ritonavir to achieve drug concentrations suitable for once-daily dosing. Coadministration of Paritaprevir with ritonavir increases the half-life of single-dose Paritaprevir from approximately 3 h to 5–8 h, doubles the time to maximum plasma concentration ( T _max) from 2.3 to 4.7 h, and increases exposures 30-fold for maximum observed plasma concentration ( C _max), 50-fold for area under the plasma concentration–time curve (AUC), and >300-fold for trough concentration ( C _24). Paritaprevir displays highly variable, nonlinear pharmacokinetics, with C _max and AUC increasing in a greater than dose proportional manner when administered with or without ritonavir. In the presence of ritonavir, Paritaprevir is excreted mostly unchanged in feces via biliary excretion. Paritaprevir exposures are higher in Japanese subjects compared with Caucasian subjects; however, no dose adjustment is needed for Japanese patients as the higher exposures are safe and well tolerated. The pharmacokinetic characteristics of Paritaprevir are similar between healthy subjects and HCV-infected patients, and are not appreciably altered by mild or moderate hepatic impairment or mild, moderate, or severe renal impairment, including those on dialysis. Paritaprevir exposures are increased in patients with severe hepatic impairment. Although the presence of a low dose of ritonavir in Paritaprevir-containing regimens increases the likelihood of drug–drug interactions, results from several drug interaction studies demonstrated that Paritaprevir-containing regimens can be coadministered with many comedications that are commonly prescribed in HCV-infected patients.

  • 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, Walid M Awni, Thomas Marbury, Lino Rodrigues, Richard A Preston, 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.

  • Population Pharmacokinetics of Paritaprevir, Ombitasvir, and Ritonavir in Japanese Patients with Hepatitis C Virus Genotype 1b Infection
    Clinical Pharmacokinetics, 2017
    Co-Authors: Sathej M. Gopalakrishnan, Amit Khatri, Akshanth R. Polepally, Sven Mensing, Rajeev M Menon
    Abstract:

    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.

Thomas Podsadecki - One of the best experts on this subject based on the ideXlab platform.

  • 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, 2017
    Co-Authors: Rajeev M Menon, Thomas Podsadecki, Walid M Awni, Nancy S Shulman, Barbara Dasilva-tillmann, Sandeep Dutta
    Abstract:

    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.

  • Effect of co-medications on Paritaprevir, ritonavir, ombitasvir, dasabuvir and ribavirin pharmacokinetics: analysis of data from seven Phase II/III trials.
    Antiviral Therapy, 2016
    Co-Authors: Akshanth R. Polepally, Thomas Podsadecki, Sandeep Dutta, Walid M Awni, Sven Mensing, Lino Rodrigues, Prajakta S Badri, Apurvasena Parikh, Barbara Da Silva-tillmann, Rajeev M Menon
    Abstract:

    BACKGROUND: The three drug direct-acting antiviral regimen (3D regimen) of ombitasvir, Paritaprevir/ritonavir and dasabuvir, with and without ribavirin, was evaluated in one Phase II trial and six Phase III trials in over 2,300 HCV genotype-1-infected patients. Patients continued taking their protocol-permitted co-medications while receiving the 3D ± ribavirin regimen. The effects of the co-medications on exposures of the 3D regimen and ribavirin were examined. METHODS: Population pharmacokinetic model-predicted steady-state area under the curve (AUC24,ss) values were evaluated in the presence/absence of the co-medications. Interactions resulting in a greater than 50% reduction or 100% increase in an AUC24,ss value were examined as covariates for an effect on apparent clearance (CL/F). RESULTS: More than 1,200 co-medications belonging to 15 drug classes and/or 19 enzyme and transporter inhibitor and/or inducer categories were used concomitantly with the 3D regimen in the trials. Approximately 1,500 patients (65%) in Phase III trials received two or more co-medications from multiple drug classes or categories. No co-medication class/category decreased or increased ombitasvir, dasabuvir, ritonavir or ribavirin AUC24,ss by more than half or twofold, respectively. Opioids, antipsychotics, anti-epileptics, antidiabetics and non-ethinyl estradiol-containing hormone replacement therapies appeared to have an effect (AUC24,ss ratio ≤0.5 or ≥2.0) on Paritaprevir exposures. However, when these classes were included in the Paritaprevir population pharmacokinetic model, only opioids and antidiabetics had a statistically significant effect on CL/F, but with no clinically meaningful increase in exposures (≤55%). CONCLUSIONS: No dose adjustment is necessary for the 3D ± ribavirin regimen when used with the co-medications included in this analysis as there were no clinically meaningful effects on exposures of the DAAs.

  • 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, 2016
    Co-Authors: Akshanth R. Polepally, Thomas Podsadecki, Sandeep Dutta, Walid M Awni, Beibei Hu, Rajeev M Menon
    Abstract:

    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.

  • Exposure-Efficacy Analyses of Ombitasvir, Paritaprevir/Ritonavir with Dasabuvir ± Ribavirin in HCV Genotype 1-Infected Patients
    Clinical Drug Investigation, 2016
    Co-Authors: Amit Khatri, Rajeev M Menon, Thomas Podsadecki, Walid M Awni, Sven Mensing, 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 (SVR12) following administration of the 3D regimen in six Phase II/III studies were examined.

  • pharmacokinetics and tolerability of Paritaprevir a direct acting antiviral agent for hepatitis c virus treatment with and without ritonavir in healthy volunteers
    British Journal of Clinical Pharmacology, 2016
    Co-Authors: Rajeev M Menon, Cheri E Klein, Thomas Podsadecki, Yilin Chiu, Sandeep Dutta, Walid M Awni
    Abstract:

    Aims Paritaprevir is a direct acting antiviral agent for use as part of a multidrug hepatitis C virus infection treatment regimen. To characterize the pharmacokinetics, safety, and tolerability of Paritaprevir and determine an optimal dosing regimen for subsequent evaluations, clinical studies were conducted with Paritaprevir alone or with ritonavir, a cytochrome P450 3A4 inhibitor anticipated to increase Paritaprevir exposure. Methods Two phase 1, double-blind, placebo-controlled, parallel group studies were conducted in healthy volunteers (NCT00850044 and NCT00931281). Single dose study participants (n = 87) were randomized to one time administration of either Paritaprevir or placebo, or Paritaprevir with ritonavir or placebo. Participants (n = 38) enrolled in the multiple dose study received Paritaprevir with ritonavir or placebo once or twice daily for 14 days. Pharmacokinetics, safety and tolerability were assessed throughout the study treatment periods. Results After single or multiple dose administration, Paritaprevir displayed non-linear pharmacokinetics, with maximum plasma concentration and area under the plasma concentration–time curve increasing in a greater than dose proportional manner. Concomitant administration of 100 mg ritonavir increased Paritaprevir exposure from a 300 mg dose approximately 30- to 50-fold and extended Paritaprevir half-life. The tolerability of Paritaprevir was similar with or without ritonavir. Asymptomatic, transient increases in bilirubin were observed but were not associated with abnormalities in other liver function tests. Conclusions Paritaprevir exhibits non-linear pharmacokinetics with greater than dose proportional increases in exposure after single or multiple dosing. Co-administration with ritonavir increases Paritaprevir exposure and half-life without adversely influencing tolerability.

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  • Clinical Pharmacokinetics of Paritaprevir
    Clinical Pharmacokinetics, 2017
    Co-Authors: Rajeev M Menon, Walid M Awni, Akshanth R. Polepally, Amit Khatri, Sandeep Dutta
    Abstract:

    Paritaprevir is a potent hepatitis C virus (HCV) nonstructural (NS) protein 3/4A protease inhibitor that is used in combination with other direct-acting antivirals (DAAs) for the treatment of chronic HCV infection. Paritaprevir is primarily metabolized by cytochrome P450 (CYP) 3A4 and is administered with a low dose of ritonavir to achieve drug concentrations suitable for once-daily dosing. Coadministration of Paritaprevir with ritonavir increases the half-life of single-dose Paritaprevir from approximately 3 h to 5–8 h, doubles the time to maximum plasma concentration ( T _max) from 2.3 to 4.7 h, and increases exposures 30-fold for maximum observed plasma concentration ( C _max), 50-fold for area under the plasma concentration–time curve (AUC), and >300-fold for trough concentration ( C _24). Paritaprevir displays highly variable, nonlinear pharmacokinetics, with C _max and AUC increasing in a greater than dose proportional manner when administered with or without ritonavir. In the presence of ritonavir, Paritaprevir is excreted mostly unchanged in feces via biliary excretion. Paritaprevir exposures are higher in Japanese subjects compared with Caucasian subjects; however, no dose adjustment is needed for Japanese patients as the higher exposures are safe and well tolerated. The pharmacokinetic characteristics of Paritaprevir are similar between healthy subjects and HCV-infected patients, and are not appreciably altered by mild or moderate hepatic impairment or mild, moderate, or severe renal impairment, including those on dialysis. Paritaprevir exposures are increased in patients with severe hepatic impairment. Although the presence of a low dose of ritonavir in Paritaprevir-containing regimens increases the likelihood of drug–drug interactions, results from several drug interaction studies demonstrated that Paritaprevir-containing regimens can be coadministered with many comedications that are commonly prescribed in HCV-infected patients.

  • 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, 2017
    Co-Authors: Rajeev M Menon, Thomas Podsadecki, Walid M Awni, Nancy S Shulman, Barbara Dasilva-tillmann, Sandeep Dutta
    Abstract:

    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.

  • 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, Walid M Awni, Thomas Marbury, Lino Rodrigues, Richard A Preston, 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.

  • Effect of co-medications on Paritaprevir, ritonavir, ombitasvir, dasabuvir and ribavirin pharmacokinetics: analysis of data from seven Phase II/III trials.
    Antiviral Therapy, 2016
    Co-Authors: Akshanth R. Polepally, Thomas Podsadecki, Sandeep Dutta, Walid M Awni, Sven Mensing, Lino Rodrigues, Prajakta S Badri, Apurvasena Parikh, Barbara Da Silva-tillmann, Rajeev M Menon
    Abstract:

    BACKGROUND: The three drug direct-acting antiviral regimen (3D regimen) of ombitasvir, Paritaprevir/ritonavir and dasabuvir, with and without ribavirin, was evaluated in one Phase II trial and six Phase III trials in over 2,300 HCV genotype-1-infected patients. Patients continued taking their protocol-permitted co-medications while receiving the 3D ± ribavirin regimen. The effects of the co-medications on exposures of the 3D regimen and ribavirin were examined. METHODS: Population pharmacokinetic model-predicted steady-state area under the curve (AUC24,ss) values were evaluated in the presence/absence of the co-medications. Interactions resulting in a greater than 50% reduction or 100% increase in an AUC24,ss value were examined as covariates for an effect on apparent clearance (CL/F). RESULTS: More than 1,200 co-medications belonging to 15 drug classes and/or 19 enzyme and transporter inhibitor and/or inducer categories were used concomitantly with the 3D regimen in the trials. Approximately 1,500 patients (65%) in Phase III trials received two or more co-medications from multiple drug classes or categories. No co-medication class/category decreased or increased ombitasvir, dasabuvir, ritonavir or ribavirin AUC24,ss by more than half or twofold, respectively. Opioids, antipsychotics, anti-epileptics, antidiabetics and non-ethinyl estradiol-containing hormone replacement therapies appeared to have an effect (AUC24,ss ratio ≤0.5 or ≥2.0) on Paritaprevir exposures. However, when these classes were included in the Paritaprevir population pharmacokinetic model, only opioids and antidiabetics had a statistically significant effect on CL/F, but with no clinically meaningful increase in exposures (≤55%). CONCLUSIONS: No dose adjustment is necessary for the 3D ± ribavirin regimen when used with the co-medications included in this analysis as there were no clinically meaningful effects on exposures of the DAAs.

  • 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, 2016
    Co-Authors: Akshanth R. Polepally, Thomas Podsadecki, Sandeep Dutta, Walid M Awni, Beibei Hu, Rajeev M Menon
    Abstract:

    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.