title: Pharmacokinetics and safety of co-administered paritaprevir plus ritonavir, ombitasvir, and dasabuvir in hepatic impairment.
abstract: OBJECTIVE
  Paritaprevir, ombitasvir, and dasabuvir are direct-acting antivirals for treatment of chronic hepatitis C virus (HCV) infection. The aim of this study was to characterize the effects of mild, moderate, and severe hepatic impairment on the pharmacokinetics of these drugs.
  
  
  METHODS
  HCV-negative subjects with normal hepatic function (n=7) or mild (Child-Pugh A, n=6), moderate (Child-Pugh B, n=6), or severe (Child-Pugh C, n=5) hepatic impairment received a single-dose of the combination of paritaprevir plus ritonavir (paritaprevir/r, 200/100 mg), ombitasvir (25 mg), and dasabuvir (400 mg). Plasma samples were collected through 144 hours after administration for pharmacokinetic assessments.
  
  
  RESULTS
  Paritaprevir, ombitasvir, dasabuvir, and ritonavir exposures (maximal plasma concentration, C(max), and area under the concentration-time curve, AUC) were minimally affected in subjects with mild or moderate hepatic impairment. Differences in exposures between healthy controls and subjects with mild or moderate hepatic impairment were less than 35%, except for 62% higher paritaprevir AUC in subjects with moderate hepatic impairment. Paritaprevir and dasabuvir AUC were significantly higher in subjects with severe hepatic impairment (950% and 325%, respectively). However, ombitasvir AUC was 54% lower and ritonavir AUC was comparable. Adverse events included eye stye, insomnia, and pain from an infiltrated intravenous line.
  
  
  CONCLUSIONS
  The changes observed in paritaprevir, ritonavir, ombitasvir, and dasabuvir exposures in subjects with mild or moderate hepatic impairment do not necessitate dose adjustment. Subjects with severe hepatic impairment had substantially higher paritaprevir and dasabuvir exposures.
authors.affiliation: AbbVie Inc., North Chicago, IL, USA. Electronic address: Amit.khatri@abbvie.com.
authors.forename: Amit
authors.initials: A
authors.lastname: Khatri
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Rajeev M
authors.initials: RM
authors.lastname: Menon
authors.affiliation: Orlando Clinical Research Center, Orlando, FL, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Marbury
authors.affiliation: Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Lawitz
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Podsadecki
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Mullally
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Bifeng
authors.initials: B
authors.lastname: Ding
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Walid M
authors.initials: WM
authors.lastname: Awni
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Barry M
authors.initials: BM
authors.lastname: Bernstein
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dutta
mesh_terms: D015081:2-Naphthylamine; D000813:Anilides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D002219:Carbamates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003521:Cyclopropanes; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D048550:Hepatic Insufficiency / Q000097:blood* / Q000209:etiology; D019698:Hepatitis C, Chronic / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D047029:Lactams, Macrocyclic; D008111:Liver Function Tests; D047028:Macrocyclic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D011392:Proline / Q000031:analogs & derivatives; D012254:Ribavirin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014633:Valine
chemical_list: D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D065692:Cytochrome P-450 CYP3A Inhibitors; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D012254:Ribavirin; D014498:Uracil; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir
keywords: Chronic hepatitis C; Dasabuvir; Direct-acting antiviral agents; Hepatic impairment; Ombitasvir; Paritaprevir; Pharmacokinetics; Ritonavir