title: Evaluation of the Pharmacokinetics and Renal Excretion of Simeprevir in Subjects with Renal Impairment.
abstract: BACKGROUND
  Simeprevir is a N3/4 protease inhibitor approved for the treatment of hepatitis C virus (HCV) infection. HCV prevalence is higher in patients with chronic kidney disease compared with the general population; safe and efficacious therapies in renal impairment are needed.
  
  
  OBJECTIVE
  To evaluate simeprevir renal excretion in healthy subjects and to compare the simeprevir steady-state pharmacokinetics between subjects with severe renal impairment and healthy subjects.
  
  
  METHODS
  In the mass balance study, healthy adults received a single 200-mg dose of (14)C-simeprevir; radioactivity in the urine and feces was quantified until concentrations were <2% of the administered dose and seven or more stools were produced. In the pharmacokinetic study, non-HCV-infected adults with severe renal impairment (estimated glomerular filtration rate ≤29 mL/min/1.73 m(2)) and matched healthy subjects (estimated glomerular filtration rate ≥80 mL/min/1.73 m(2)) received 150 mg simeprevir for 7 days. Pharmacokinetic analysis was performed post-dose on Day 7.
  
  
  RESULTS
  (14)C-simeprevir recovery from the urine was low (0.009-0.138% of total dose). The minimum plasma concentration, maximum plasma concentration, and area under the plasma concentration-time curve at 24 h were 71, 34, and 62% higher, respectively, in subjects with severe renal impairment compared with healthy subjects. The mean fraction of simeprevir unbound to protein was <0.0001 (all subjects). Most adverse events were grade I or II; one subject with renal impairment who was receiving fenofibrate presented with grade 3 rhabdomyolysis.
  
  
  CONCLUSIONS
  Simeprevir plasma concentrations were mildly elevated in subjects with severe renal impairment. The results suggest that simeprevir may be administered without dose adjustment in patients with renal impairment.
authors.affiliation: Janssen Research & Development, Turnhoutseweg 30, Beerse, 2340, Belgium, SOUWERKE@its.jnj.com.
authors.forename: Sivi
authors.initials: S
authors.lastname: Ouwerkerk-Mahadevan
authors.forename: Maria
authors.initials: M
authors.lastname: Beumont-Mauviel
authors.forename: Steven
authors.initials: S
authors.lastname: Mortier
authors.forename: Monika
authors.initials: M
authors.lastname: Peeters
authors.forename: Rene
authors.initials: R
authors.lastname: Verloes
authors.forename: Carla
authors.initials: C
authors.lastname: Truyers
authors.forename: Geert
authors.initials: G
authors.lastname: Mannens
authors.forename: Inneke
authors.initials: I
authors.lastname: Wynant
authors.forename: Alexandru
authors.initials: A
authors.lastname: Simion
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002250:Carbon Radioisotopes / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine*; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011480:Protease Inhibitors / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D051437:Renal Insufficiency / Q000378:metabolism / Q000652:urine*; D000069616:Simeprevir / Q000032:analysis / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine*; D055815:Young Adult
chemical_list: D002250:Carbon Radioisotopes; D011480:Protease Inhibitors; D000069616:Simeprevir