title: Effects of chronic renal failure on the pharmacokinetics of ruboxistaurin and its active metabolite 338522.
abstract: BACKGROUND
  Ruboxistaurin, a specific inhibitor of the beta(1) and beta(2) isoforms of protein kinase C, is currently in clinical development for the treatment of several diabetic microvascular complications. The major metabolite, N-desmethyl ruboxistaurin (metabolite 338522), is equipotent in its inhibitory activity. The elimination of ruboxistaurin and its metabolites is primarily through bile and the faecal route, with urinary excretion constituting only a minor route.
  
  
  OBJECTIVE
  To assess the effects of chronic renal insufficiency on the pharmacokinetics of ruboxistaurin and metabolite 338522.
  
  
  METHODS
  Six healthy subjects (creatinine clearance >80 mL/min/1.73 m(2)) and six end-stage renal disease (ESRD) subjects requiring long-term haemodialysis were studied. All subjects received a single oral dose of ruboxistaurin 32 mg followed by serial blood sampling up to 72 hours. ESRD subjects underwent haemodialysis approximately 58 hours after dosing, with blood samples obtained immediately before and after dialysis.
  
  
  RESULTS
  No differences were observed in the pharmacokinetic parameters (area under the plasma concentration-time curve from time zero to infinity [AUC(infinity)], maximum plasma concentration [C(max)] and elimination half-life [t(1/2)]) of ruboxistaurin and metabolite 338522 between healthy and ESRD subjects Plasma concentrations of ruboxistaurin were below the lower limit of quantification by the time of haemodialysis. The predicted post-dialysis plasma concentrations of metabolite 338522 were not statistically different from the observed values (p=0.163). Ruboxistaurin was well tolerated in both groups of subjects.
  
  
  CONCLUSIONS
  These results indicate that the kidney is not an important route of metabolism or excretion for ruboxistaurin and metabolite 338522. Based on the pharmacokinetic and tolerability findings, no formal dosage adjustment of ruboxistaurin should be required for patients with any degree of renal impairment who are undergoing haemodialysis.
authors.affiliation: Lilly-NUS Centre for Clinical Pharmacology, National University of Singapore, Singapore. sdw@lilly.com
authors.forename: Stephen
authors.initials: S
authors.lastname: Wise
authors.forename: Eunice
authors.initials: E
authors.lastname: Yuen
authors.forename: Clark
authors.initials: C
authors.lastname: Chan
authors.forename: Yeo Kwee
authors.initials: YK
authors.lastname: Poo
authors.forename: Lorraine
authors.initials: L
authors.lastname: Teng
authors.forename: Titus
authors.initials: T
authors.lastname: Lau
authors.forename: James
authors.initials: J
authors.lastname: Voelker
mesh_terms: D000328:Adult; D000465:Algorithms; D019540:Area Under Curve; D001711:Biotransformation; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics*; D007676:Kidney Failure, Chronic / Q000378:metabolism* / Q000628:therapy; D008297:Male; D008301:Maleimides / Q000009:adverse effects / Q000493:pharmacokinetics*; D006435:Renal Dialysis
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; C474461:LY 338522; D008301:Maleimides; C099154:ruboxistaurin