title: Population Pharmacokinetics of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin in Patients with Hepatitis C Virus Genotype 1 Infection: Combined Analysis from 9 Phase 1b/2 Studies.
abstract: Direct-acting antiviral agents (DAAs) are established as the standard of care for chronic hepatitis C virus (HCV) infection. One of the newest additions to the HCV arsenal is an oral three-DAA combination therapy (i.e., the 3D regimen) that does not require concomitant use of pegylated interferon. The clinical development program for the 3D regimen has yielded a robust dataset that is inclusive of various dosing schemes and a diverse patient population. Using data from nine phase 1b/2a/2b studies that enrolled patients with HCV genotype 1 infection, population pharmacokinetic models were developed for each component of the 3D regimen (ombitasvir, paritaprevir, ritonavir, and dasabuvir) and for ribavirin, an adjunctive therapy used to enhance therapeutic efficacy in some populations. Formulation effects, accumulation, relative bioavailability, and interactions between DAAs were assessed during model development, and demographic and clinical covariates were identified and evaluated for their effects on drug exposures. Proposed models were assessed via goodness-of-fit plots, visual predictive checks, and bootstrap evaluations. Population pharmacokinetic models adequately described their respective plasma concentration-time data with precise and reliable model parameter estimates and with good predictive performance. Covariates, including age, sex, body weight, cytochrome P450 2C8 inhibitor use, non-Hispanic ethnicity, and creatinine clearance, were associated with apparent clearance and/or apparent volume parameters; however, the magnitude of effect on drug exposure was modest and not considered to be clinically significant. No patient-related or clinical parameters were identified that would necessitate dose adjustment of the 3D regimen in patients with HCV genotype 1 infection.
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67065, Ludwigshafen am Rhein, Germany. sven.mensing@abbvie.com.
authors.forename: Sven
authors.initials: S
authors.lastname: Mensing
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Akshanth R
authors.initials: AR
authors.lastname: Polepally
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67065, Ludwigshafen am Rhein, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: König
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Khatri
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Podsadecki
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Walid M
authors.initials: WM
authors.lastname: Awni
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Rajeev M
authors.initials: RM
authors.lastname: Menon
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dutta
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001682:Biological Availability; D001835:Body Weight; D002626:Chemistry, Pharmaceutical; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011153:Population; D012737:Sex Factors; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D065607:Cytochrome P-450 Enzyme Inhibitors
keywords: 2D regimen; 3D regimen; direct-acting antiviral; dosing recommendations; population pharmacokinetics