title: Exposure-Safety Response Relationship for Ombitasvir, Paritaprevir/Ritonavir, Dasabuvir, and Ribavirin in Patients with Chronic Hepatitis C Virus Genotype 1 Infection: Analysis of Data from Five Phase II and Six Phase III Studies.
abstract: OBJECTIVE
  All-oral direct-acting antiviral regimens that include combinations of ombitasvir, paritaprevir, ritonavir, and dasabuvir with or without ribavirin were evaluated in hepatitis C virus-infected patients in phase II/III clinical studies. The objective of these analyses was to quantify the relationship between exposures of the components of the regimen and laboratory values and to determine covariates that could influence the relationship.
  
  
  METHODS
  Exposure-safety response relationships between individual components of the direct-acting antiviral regimens and clinically important laboratory values were explored using data from 2998 patients from 11 phase II/III clinical studies. Multivariate logistic regression analyses were used to identify significant relationships between predictor variables and response variables.
  
  
  RESULTS
  No statistically significant associations were observed between ombitasvir, dasabuvir, or ritonavir exposures and maximum post-baseline alanine aminotransferase (ALT) or total bilirubin grade or minimum hemoglobin grade. A two-fold increase in paritaprevir exposure from therapeutic exposure was predicted to increase the probability of experiencing a grade 3 or higher increase in ALT by 0.5% and bilirubin by 1.1%. In the phase II/III clinical studies, ALT and bilirubin increases were reversible with continued dosing or after treatment cessation. Other correlates with adverse events of clinical importance included concomitant ribavirin treatment, sex, race, and presence of cirrhosis, consistent with previous observations.
  
  
  CONCLUSIONS
  Exposure-response analyses from phase II/III studies with the combination direct-acting antiviral regimen indicated no statistically significant relationships with ombitasvir, dasabuvir, or ritonavir exposure, but a statistically significant association was observed between paritaprevir exposure and the probability of experiencing a grade 3 or higher increase in ALT or bilirubin.
authors.affiliation: Research and Development, Clinical Pharmacology and Pharmacometrics, AbbVie, Inc., Department R4PK, Building AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Lin
authors.affiliation: Research and Development, Clinical Pharmacology and Pharmacometrics, AbbVie, Inc., Department R4PK, Building AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA. rajeev.menon@abbvie.com.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Menon
authors.affiliation: Research and Development, Clinical Pharmacology and Pharmacometrics, AbbVie, Inc., Department R4PK, Building AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Research and Development, Clinical Pharmacology and Pharmacometrics, AbbVie, Inc., Department R4PK, Building AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Podsadecki
authors.affiliation: Research and Development, Clinical Pharmacology and Pharmacometrics, AbbVie, Inc., Department R4PK, Building AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Shulman
authors.affiliation: Research and Development, Clinical Pharmacology and Pharmacometrics, AbbVie, Inc., Department R4PK, Building AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: DaSilva-Tillmann
authors.affiliation: Research and Development, Clinical Pharmacology and Pharmacometrics, AbbVie, Inc., Department R4PK, Building AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Walid
authors.initials: W
authors.lastname: Awni
authors.affiliation: Research and Development, Clinical Pharmacology and Pharmacometrics, AbbVie, Inc., Department R4PK, Building AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dutta
mesh_terms: D015081:2-Naphthylamine; D000293:Adolescent; D000328:Adult; D000368:Aged; D000813:Anilides / Q000008:administration & dosage; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002219:Carbamates / Q000008:administration & dosage; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D011392:Proline / Q000031:analogs & derivatives; D012254:Ribavirin / Q000627:therapeutic use; D019438:Ritonavir / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D014633:Valine; D055815:Young Adult
chemical_list: D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; 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