Population Pharmacokinetics of Paritaprevir, Ombitasvir, and Ritonavir in Japanese Patients with Hepatitis C Virus Genotype 1b Infection

• Published in: Clinical pharmacokinetics Vol. 56; no. 1; pp. 1 - 10
• Main Authors: Gopalakrishnan, Sathej M., Polepally, Akshanth R., Mensing, Sven, Khatri, Amit, Menon, Rajeev M.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 2017; Springer Nature B.V
• Subjects: Adolescent; Adult; Aged; Anilides - pharmacokinetics; Anilides - therapeutic use; Antiretroviral drugs; Antiviral Agents - administration & dosage; Antiviral Agents - pharmacokinetics; Antiviral Agents - therapeutic use; Antiviral drugs; Carbamates - pharmacokinetics; Carbamates - therapeutic use; Clinical trials; Double-Blind Method; Drug dosages; Drug Therapy, Combination; Female; Fibrosis - epidemiology; Genotype; Genotype & phenotype; Hepacivirus - genetics; Hepatitis; Hepatitis C; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - epidemiology; Humans; Infections; Interferon; Internal Medicine; Japan; Leading Article; Liver cancer; Macrocyclic Compounds - pharmacokinetics; Macrocyclic Compounds - therapeutic use; Male; Medicine; Medicine & Public Health; Metabolic Clearance Rate; Middle Aged; Models, Biological; Patients; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Population; Renal Insufficiency - epidemiology; Ritonavir - pharmacokinetics; Ritonavir - therapeutic use; Sex Factors; Studies; Young Adult; Japan; Population Pharmacokinetic Model; Telaprevir; Visual Predictive Check; Ritonavir; Breast Cancer Resistance Protein
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-016-0423-2

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.