title: Effects of Mild and Moderate Renal Impairment on Ombitasvir, Paritaprevir, Ritonavir, Dasabuvir, and Ribavirin Pharmacokinetics in Patients with Chronic HCV Infection.
abstract: OBJECTIVE
  Ombitasvir, paritaprevir (given with low-dose ritonavir), and dasabuvir are direct-acting antivirals (DAAs) used with or without ribavirin for the treatment of chronic hepatitis C virus (HCV) infection. The objective of this analysis was to evaluate the effect of renal function as determined by creatinine clearance (CrCL) on the pharmacokinetics of the DAAs, ritonavir, and ribavirin in HCV genotype 1-infected patients with or without cirrhosis.
  
  
  METHODS
  Total exposure, measured by area under the plasma concentration-time curve (AUC), was generated for the DAAs, ritonavir, and ribavirin using population pharmacokinetic modeling of data (N = 2093 patients) from 6 Phase 3 studies and 1 Phase 2 study. The effect of CrCL on the AUC values of each DAA, ritonavir, and ribavirin was separately evaluated and adjusted for any significant patient-specific covariates including, age, sex, body weight, cirrhosis, and Asian race in multiple linear regression analysis. Using the final models, AUC values were predicted for patients with normal renal function (CrCL = 105 mL/min), mild renal impairment (CrCL = 75 mL/min) and moderate renal impairment (CrCL = 45 mL/min).
  
  
  RESULTS
  CrCL was not a statistically significant predictor of DAA or ritonavir AUC values. Age, sex, and cirrhosis were significant covariates for the AUC values of all the DAAs and body weight was a significant covariate for the AUC values of ombitasvir and dasabuvir. Asian race was significant only for dasabuvir. Only age and sex were statistically significant predictors for the AUC values of ritonavir. CrCL showed a significant relationship with the ribavirin AUC values, consistent with ribavirin's renal excretion. Age, sex, body weight, and cirrhosis were also significant covariates for the AUC values of ribavirin. The DAA and ritonavir AUC values were comparable (≤10 % difference) among different levels of renal function, while ribavirin AUC values were up to 17 % higher in mild/moderate renal impairment compared with normal renal function.
  
  
  CONCLUSIONS
  No dose adjustments are needed for the 3D regimen in HCV genotype-1 infected patients with mild or moderate renal impairment. Ribavirin doses should be adjusted for renal impairment as recommended in the ribavirin label.
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Dept. R4PK, AbbVie Inc., Bldg. AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA. akshanth.r.polepally@abbvie.com.
authors.forename: Akshanth R
authors.initials: AR
authors.lastname: Polepally
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Dept. R4PK, AbbVie Inc., Bldg. AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Prajakta S
authors.initials: PS
authors.lastname: Badri
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany.
authors.forename: Doerthe
authors.initials: D
authors.lastname: Eckert
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Mensing
authors.affiliation: Clinical Pharmacology and Pharmacometrics, Dept. R4PK, AbbVie Inc., Bldg. AP31-3, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Rajeev M
authors.initials: RM
authors.lastname: Menon
mesh_terms: D015081:2-Naphthylamine; D000293:Adolescent; D000328:Adult; D000368:Aged; D000813:Anilides / Q000008:administration & dosage / Q000493:pharmacokinetics; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002219:Carbamates / Q000008:administration & dosage / Q000493:pharmacokinetics; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000821:virology; D006801:Humans; D007677:Kidney Function Tests; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011392:Proline / Q000031:analogs & derivatives; D051437:Renal Insufficiency / Q000150:complications*; D012254:Ribavirin / Q000008:administration & dosage / Q000493:pharmacokinetics; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; 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