Dose- and Formulation-Dependent Non-Linear Pharmacokinetic Model of Paritaprevir, a Protease Inhibitor for the Treatment of Hepatitis C Virus Infection: Combined Analysis from 12 Phase I Studies

• Published in: Clinical pharmacokinetics Vol. 55; no. 9; pp. 1091 - 1101
• Main Authors: Polepally, Akshanth R., Mensing, Sven, Khatri, Amit, Beck, Denise, Liu, Wei, Awni, Walid M., Menon, Rajeev M., Dutta, Sandeep
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.09.2016; Springer Nature B.V
• Subjects: Adolescent; Adult; Antiviral Agents - administration & dosage; Antiviral Agents - blood; Antiviral Agents - pharmacokinetics; Biological Availability; Drug Compounding - methods; Drug Interactions; Drug Therapy, Combination; Female; Healthy Volunteers; Hepacivirus - genetics; Hepatitis C - drug therapy; Humans; Internal Medicine; Macrocyclic Compounds - administration & dosage; Macrocyclic Compounds - blood; Macrocyclic Compounds - pharmacokinetics; Macrocyclic Compounds - therapeutic use; Male; Medicine; Medicine & Public Health; Middle Aged; Models, Biological; Original Research Article; Pharmacology/Toxicology; Pharmacotherapy; Protease Inhibitors - therapeutic use; Ribavirin; Ritonavir - administration & dosage; Ritonavir - pharmacokinetics; Ritonavir - therapeutic use; Young Adult; Objective Function Value; Population Pharmacokinetic Model; Ritonavir; Population Pharmacokinetic Analysis; Breast Cancer Resistance Protein
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-016-0385-4

Background and Objectives Paritaprevir is a direct-acting antiviral agent that is a component of approved multidrug regimens used in the treatment of hepatitis C virus (HCV) infection. A population pharmacokinetic model for paritaprevir was developed using data from formulation, bioavailability, and drug–drug interaction studies that evaluated the pharmacokinetics of paritaprevir (coadministered with ritonavir to enhance exposure) with or without ombitasvir and/or dasabuvir at different paritaprevir dose levels. Methods A non-linear mixed-effects modeling approach was applied to data from 12 phase I, single- and multiple-dose studies that enrolled a total of 369 healthy volunteers. Age, sex, race, ethnicity, body weight, body surface area, body mass index, and baseline creatinine clearance were evaluated as covariates during model development. In addition, the influences of dose, formulation, and concomitant medications (e.g. ombitasvir and dasabuvir) on paritaprevir bioavailability were included in the model. Results A two-compartment model with first-order absorption and elimination optimally described paritaprevir plasma concentration–time data. Paritaprevir bioavailability was formulation- and dose-dependent, and increased supraproportionally. The accumulation of paritaprevir was 1.57-fold on repeated dosing compared with the first dose. Coadministration of dasabuvir increased paritaprevir bioavailability by 59 %; however, ombitasvir coadministration did not affect the pharmacokinetic profile of paritaprevir. No subject-specific covariate influenced the paritaprevir pharmacokinetics. The pharmacokinetic model was robust in bootstrap evaluations and was consistent with observed data based on diagnostic goodness-of-fit plots and visual predictive checks. Conclusion The complex pharmacokinetics of paritaprevir were well described by the model, which can be used as a basis for clinical trial dosing and further evaluations in patients with HCV.