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

摘要

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.