Sathej Gopalakrishnan1, Sven Mensing1, Rajeev M Menon2, Jiuhong Zha3. 1. Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen am Rhein, Germany. 2. Clinical Pharmacology and Pharmacometrics, AbbVie Inc., Building AP31-3, 1 North Waukegan Rd., North Chicago, IL, 60064, USA. 3. Clinical Pharmacology and Pharmacometrics, AbbVie Inc., Building AP31-3, 1 North Waukegan Rd., North Chicago, IL, 60064, USA. jiuhong.zha@abbvie.com.
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. OBJECTIVE: The current analysis aimed to characterize the population pharmacokinetics in patients without cirrhosis ('non-cirrhotic') and with compensated cirrhosis ('cirrhotic'), while accounting for differences across hepatitis C virus (HCV) genotypes (GT) 1, 2, and 4, multiple regimens (3D regimen ± ribavirin for GT1 in global studies, 2D regimen for subgenotype 1b in Japan, 2D regimen + ribavirin for GT2 in Japan, and 2D regimen + ribavirin for GT4), and ethnicities. METHODS: Pharmacokinetic data from nine clinical studies (~ 1850 patients) were used to model the population pharmacokinetics of each component of the DAA regimens. Model development was performed in stages, starting with an initial base model. Covariate-parameter relationships were then assessed using forward inclusion/backward elimination procedures. Model development was guided by goodness-of-fit plots, likelihood ratio tests, plausibility of parameter estimates, and knowledge of DAA, ritonavir, and ribavirin pharmacokinetics. Paritaprevir, ombitasvir, and ritonavir pharmacokinetics were described by a one-compartment model, while dasabuvir and ribavirin pharmacokinetics were characterized by a two-compartment model. RESULTS: The analysis showed generally overlapping exposures between compensated cirrhotic and non-cirrhotic patients or between subgroups of the identified significant covariates. The largest differences were the approximately 30-60% higher dasabuvir and paritaprevir exposures in compensated cirrhotic patients. CONCLUSION: These differences did not warrant dose adjustments for the DAAs when used in HCV-infected patients with compensated cirrhosis.
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. OBJECTIVE: The current analysis aimed to characterize the population pharmacokinetics in patients without cirrhosis ('non-cirrhotic') and with compensated cirrhosis ('cirrhotic'), while accounting for differences across hepatitis C virus (HCV) genotypes (GT) 1, 2, and 4, multiple regimens (3D regimen ± ribavirin for GT1 in global studies, 2D regimen for subgenotype 1b in Japan, 2D regimen + ribavirin for GT2 in Japan, and 2D regimen + ribavirin for GT4), and ethnicities. METHODS: Pharmacokinetic data from nine clinical studies (~ 1850 patients) were used to model the population pharmacokinetics of each component of the DAA regimens. Model development was performed in stages, starting with an initial base model. Covariate-parameter relationships were then assessed using forward inclusion/backward elimination procedures. Model development was guided by goodness-of-fit plots, likelihood ratio tests, plausibility of parameter estimates, and knowledge of DAA, ritonavir, and ribavirin pharmacokinetics. Paritaprevir, ombitasvir, and ritonavir pharmacokinetics were described by a one-compartment model, while dasabuvir and ribavirin pharmacokinetics were characterized by a two-compartment model. RESULTS: The analysis showed generally overlapping exposures between compensated cirrhotic and non-cirrhotic patients or between subgroups of the identified significant covariates. The largest differences were the approximately 30-60% higher dasabuvir and paritaprevir exposures in compensated cirrhotic patients. CONCLUSION: These differences did not warrant dose adjustments for the DAAs when used in HCV-infectedpatients with compensated cirrhosis.
Authors: Jacob Lalezari; J Greg Sullivan; Peter Varunok; Edward Galen; Kris V Kowdley; Vinod Rustgi; Humberto Aguilar; Franco Felizarta; Barbara McGovern; Martin King; Akshanth R Polepally; Daniel E Cohen Journal: J Hepatol Date: 2015-04-01 Impact factor: 25.083
Authors: Jordan J Feld; Christophe Moreno; Roger Trinh; Edward Tam; Stefan Bourgeois; Yves Horsmans; Magdy Elkhashab; David E Bernstein; Ziad Younes; Robert W Reindollar; Lois Larsen; Bo Fu; Kevin Howieson; Akshanth R Polepally; Andreas Pangerl; Nancy S Shulman; Fred Poordad Journal: J Hepatol Date: 2015-10-22 Impact factor: 25.083
Authors: Jordan J Feld; Kris V Kowdley; Eoin Coakley; Samuel Sigal; David R Nelson; Darrell Crawford; Ola Weiland; Humberto Aguilar; Junyuan Xiong; Tami Pilot-Matias; Barbara DaSilva-Tillmann; Lois Larsen; Thomas Podsadecki; Barry Bernstein Journal: N Engl J Med Date: 2014-04-10 Impact factor: 91.245
Authors: Ron J Keizer; Robert S Jansen; Hilde Rosing; Bas Thijssen; Jos H Beijnen; Jan H M Schellens; Alwin D R Huitema Journal: Pharmacol Res Perspect Date: 2015-03-25