title: The pharmacokinetics of cerivastatin in patients on chronic hemodialysis.
abstract: OBJECTIVE
  The single-dose and steady-state pharmacokinetics of the HMG-CoA reductase inhibitor cerivastatin and its two major metabolites, M-1 and M-23, were evaluated in patients with renal failure on chronic hemodialysis.
  
  
  METHODS
  After having given their informed consent, 12 end-stage renal disease patients (5 female/7 male; 18 to 63 years) received a single-dose of 0.2 mg cerivastatin sodium followed by a 4-hour dialysis session for pharmacokinetic profiling. Two to four weeks later, all patients received 0.2 mg once-daily as maintenance treatment for a period of 7 days during which PK profiling was carried out on Days 1 and 7/8, both being dialysis-free days. Plasma concentrations of parent drug and active metabolites were measured by HPLC with fluorescence detection. In addition, assessment of lipid parameters, safety and tolerability, and a complete clinical chemistry program were included in the study procedures.
  
  
  RESULTS
  Cerivastatin was well-tolerated and no serious adverse events were observed. In spite of the short treatment period, treatment responses with respect to total cholesterol, LDL cholesterol and triglycerides lowering were observed. Mean cerivastatin and metabolite concentrations and thus systemic exposure were slightly higher (up to 50%) in patients on chronic dialysis compared to previous studies carried out in healthy subjects. The unbound fraction of cerivastatin ranged from 0.6 - 1.5% in these patients (normal range: 0.5 - 0.9%). The half-lives of both parent drug (approximately 3 h) and metabolites remained unaffected and, most notably, no accumulation occurred under repeated dosing. In addition, cerivastatin clearance was not increased by concurrent dialysis as would be predicted from the high plasma protein-binding (> 99%), and there were no significant differences in cerivastatin exposure between the dialysis period and the dialysis-free profile days.
  
  
  CONCLUSIONS
  Cerivastatin can be safely administered in the usual dosages to patients with end-stage renal disease on chronic hemodialysis. Based on the observed moderate increase in cerivastatin mean exposure, patients should be started at the lower end of the recommended dosing range and subsequent titration should be performed with caution.
authors.affiliation: Institute of Clinical Pharmacology, Bayer AG, Wuppertal, Germany. Wolfgang.Mueck.WM@bayer-ag.de
authors.forename: W
authors.initials: W
authors.lastname: Mück
authors.forename: S
authors.initials: S
authors.lastname: Park
authors.forename: W
authors.initials: W
authors.lastname: Jäger
authors.forename: B
authors.initials: B
authors.lastname: Voith
authors.forename: E
authors.initials: E
authors.lastname: Wandel
authors.forename: P R
authors.initials: PR
authors.lastname: Galle
authors.forename: A
authors.initials: A
authors.lastname: Schwarting
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D002784:Cholesterol / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006207:Half-Life; D006439:Hemodynamics; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics*; D006435:Renal Dialysis
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; D002784:Cholesterol; C086276:cerivastatin