title: Exposure-Response Relationship for Ombitasvir and Paritaprevir/Ritonavir in Hepatitis C Virus Subgenotype 1b-Infected Japanese Patients in the Phase 3 Randomized GIFT-I Study.
abstract: The all-oral 2 direct-acting antiviral (DAA) regimen of ombitasvir/paritaprevir/ritonavir 25/150/100 mg once a day has been evaluated in hepatitis C virus subgenotype 1b-infected Japanese adults in the GIFT-I study. The aim of this analysis was to evaluate potential relationships between DAA exposures and laboratory abnormalities/adverse events of peripheral edema in patients in GIFT-I.
  
  
  
  The GIFT-I study consisted of a randomized, double-blind, placebo-controlled substudy in patients without cirrhosis and an open-label substudy in patients with compensated cirrhosis. Patients received ombitasvir/paritaprevir/ritonavir for 12 weeks. Exposure-response relationships between individual components of the ombitasvir/paritaprevir/ritonavir regimen and clinical parameters of interest were explored using pharmacokinetic and clinical data from patients in the study. Graphical analyses were performed. For events that occurred in at least 10 patients (total bilirubin elevation ≥grade 2 and peripheral edema ≥grade 1), multivariate logistic regression analyses were used to identify significant relationships between predictor variables (drug exposures) and response variables (probability of adverse events or laboratory abnormalities), with consideration for the effect of potential covariates and baseline status of response variables.
  
  
  
  Data from 321 noncirrhotic and 42 compensated cirrhotic patients were analyzed. There were 14 events of peripheral edema (10 at grade 1 and 4 at grade 2) in patients who received concomitant administration of calcium channel blockers and ombitasvir/paritaprevir/ritonavir. There was no apparent relationship between the incidences of peripheral edema and exposures of paritaprevir, ombitasvir, or ritonavir. There was a shallow relationship between total bilirubin elevation and exposures of paritaprevir which is an inhibitor of bilirubin transporter organic anion-transporting polypeptide 1B. Based on graphical analyses, exposures of paritaprevir, ombitasvir, or ritonavir were weakly associated with hemoglobin decrease, but not associated with post baseline alanine aminotransferase or aspartate aminotransferase elevations.
  
  
  
  In Japanese patients, there were no associations or only shallow relationships between DAA exposures and peripheral edema or laboratory abnormalities. Consequently, therapeutic drug monitoring is not expected to be beneficial in managing patients on the 2-DAA regimen.
  
  
  
  ClinicalTrials.gov identifier, NCT02023099.
  
  
  
  AbbVie Inc.
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co KG, Ludwigshafen am Rhein, Germany.
authors.forename: Sathej
authors.initials: S
authors.lastname: Gopalakrishnan
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Khatri
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co KG, Ludwigshafen am Rhein, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Mensing
authors.affiliation: Global Pharmaceutical Research and Development, AbbVie Inc., North Chicago, IL, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Redman
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Menon
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA. jiuhong.zha@abbvie.com.
authors.forename: Jiuhong
authors.initials: J
authors.lastname: Zha
mesh_terms: D000328:Adult; D000368:Aged; D000813:Anilides / Q000008:administration & dosage / Q000009:adverse effects; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects; D003521:Cyclopropanes; D004311:Double-Blind Method; D016903:Drug Monitoring / Q000379:methods; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D005814:Genes, Viral; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000453:epidemiology / Q000821:virology; D006801:Humans; D007564:Japan / Q000453:epidemiology; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D011392:Proline / Q000031:analogs & derivatives; D019438:Ritonavir / Q000008:administration & dosage / Q000009:adverse effects; D013449:Sulfonamides; D016896:Treatment Outcome; D014633:Valine
chemical_list: D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D011392:Proline; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir
keywords: Exposure–Response; Hepatitis C virus; Ombitasvir; Paritaprevir