title: Single-dose pharmacokinetics and safety of daclatasvir in subjects with renal function impairment.
abstract: BACKGROUND
  Daclatasvir (DCV) is a pangenotypic inhibitor of the HCV NS5A replication complex approved in Japan and Europe for combination treatment of HCV. AI444-063 was an open-label, two-stage, adaptive study assessing DCV pharmacokinetics and safety in HCV-uninfected subjects with renal impairment.
  
  
  METHODS
  Stage 1 included 12 subjects with end-stage renal disease (ESRD) on dialysis and 12 healthy controls (creatinine clearance [CLcr]≥90 ml/min, Cockcroft-Gault) matched by sex, age and weight. All participants received a single DCV 60-mg dose on day 1. DCV plasma levels were measured through day 4. Prespecified criteria for study expansion (ESRD versus control area under the curve extrapolated to infinite time [AUC∞] geometric mean ratio [GMR] upper 90% CI>1.5) were met; therefore, 12 subjects with moderate or severe renal impairment (estimated glomerular filtration rate, 30-59 and 15-29 ml/min/1.73m(2), respectively) were included in stage 2.
  
  
  RESULTS
  All 36 participants (30 male, mean age 54 years) completed the study. DCV AUC∞ was higher in ESRD subjects versus controls (GMR 1.264, 90% CI 0.989, 1.616). Compared with normal CLcr (90 ml/min), GMR and 90% CI for unbound DCV AUC∞ at CLcr 60, 30 and 15 ml/min were 1.18 (1.07, 1.30), 1.39 (1.14, 1.70) and 1.51 (1.18, 1.94), respectively. DCV was generally well tolerated in subjects with normal renal function, ESRD, or moderate or severe renal impairment.
  
  
  CONCLUSIONS
  Observed DCV exposure increases were within the normal range of variability and were not associated with an elevated risk of adverse events. DCV can be administered in subjects with renal impairment, including ESRD, without dose modification. ClinicalTrials.gov NCT01830205.
authors: Bristol-Myers Squibb Research and Development, Princeton, NJ, USA. tushar.garimella@bms.com.
authors: Tushar
authors: T
authors: Garimella
authors: Reena
authors: R
authors: Wang
authors: Wen-Lin
authors: WL
authors: Luo
authors: Carey
authors: C
authors: Hwang
authors: Diane
authors: D
authors: Sherman
authors: Hamza
authors: H
authors: Kandoussi
authors: Thomas C
authors: TC
authors: Marbury
authors: Harry
authors: H
authors: Alcorn
authors: Richard
authors: R
authors: Bertz
authors: Marc
authors: M
authors: Bifano
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002219:Carbamates; D005260:Female; D005919:Glomerular Filtration Rate / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007676:Kidney Failure, Chronic / Q000150:complications*; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D014633:Valine / Q000031:analogs & derivatives; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; D014633:Valine; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C549273:daclatasvir