title: Pharmacokinetics of the oral direct renin inhibitor aliskiren alone and in combination with irbesartan in renal impairment.
abstract: BACKGROUND
  Aliskiren is an orally active direct renin inhibitor approved for the treatment of hypertension. This study assessed the effects of renal impairment on the pharmacokinetics and safety of aliskiren alone and in combination with the angiotensin receptor antagonist irbesartan.
  
  
  METHODS
  This open-label study enrolled 17 males with mild, moderate or severe renal impairment (creatinine clearance [CL(CR)] 50-80, 30-49 and <30 mL/minute, respectively) and 17 healthy males matched for age and bodyweight. Subjects received oral aliskiren 300 mg once daily on days 1-7 and aliskiren coadministered with irbesartan 300 mg on days 8-14. Plasma aliskiren concentrations were determined by high-performance liquid chromatography/tandem mass spectrometry at frequent intervals up to 24 hours after dosing on days 1, 7 and 14.
  
  
  RESULTS
  Renal clearance of aliskiren averaged 1280 +/- 500 mL/hour (mean +/- SD) in healthy subjects and 559 +/- 220, 312 +/- 75 and 243 +/- 186 mL/hour in patients with mild, moderate and severe renal impairment, respectively. At steady state (day 7), the geometric mean ratios (renal impairment : matched healthy volunteers) ranged from 1.21 to 2.05 for the area under the plasma concentration-time curve (AUC) over the dosage interval tau (24h) [AUC(tau)]) and from 0.83 to 2.25 for the maximum observed plasma concentration of aliskiren at steady state. Changes in exposure did not correlate with CL(CR), consistent with an effect of renal impairment on non-renal drug disposition. The observed large intersubject variability in aliskiren pharmacokinetic parameters was unrelated to the degree of renal impairment. Accumulation of aliskiren at steady state (indicated by the AUC from 0 and 24 hours [AUC(24)] on day 7 vs day 1) was similar in healthy subjects (1.79 [95% CI 1.24, 2.60]) and those with renal impairment (range 1.39-1.99). Coadministration with irbesartan did not alter the pharmacokinetics of aliskiren. Aliskiren was well tolerated when administered alone or with irbesartan.
  
  
  CONCLUSIONS
  Exposure to aliskiren is increased by renal impairment but does not correlate with the severity of renal impairment (CL(CR)). This is consistent with previous data indicating that renal clearance of aliskiren represents only a small fraction of total clearance. Initial dose adjustment of aliskiren is unlikely to be required in patients with renal impairment.
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
authors.forename: Sujata
authors.initials: S
authors.lastname: Vaidyanathan
authors.forename: Hilde
authors.initials: H
authors.lastname: Bigler
authors.forename: ChingMing
authors.initials: C
authors.lastname: Yeh
authors.forename: Marie-Noelle
authors.initials: MN
authors.lastname: Bizot
authors.forename: Hans Armin
authors.initials: HA
authors.lastname: Dieterich
authors.forename: Dan
authors.initials: D
authors.lastname: Howard
authors.forename: William P
authors.initials: WP
authors.lastname: Dole
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004359:Drug Therapy, Combination; D005650:Fumarates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D000077405:Irbesartan; D007674:Kidney Diseases / Q000188:drug therapy*; D010599:Pharmacokinetics; D013777:Tetrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D001713:Biphenyl Compounds; D005650:Fumarates; D000077405:Irbesartan; D013777:Tetrazoles; D000092502:Renin Inhibitors; C446481:aliskiren