The pharmacokinetics of cerivastatin in patients on chronic hemodialysis

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 eleven their informed consent, 12 end-stage renal dis ease 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 pharmac okinetic profiling. Two to four weeks later, all patients received 0.2 mg o nce-daily as maintenance treatment for a period of 7 days during which PK p rofiling was carried out on Days I and 7/8, both being dialysis-free days. Plasma concentrations of parent drug and active metabolites were measured b y HPLC with fluorescence detection. In addition, assessment of lipid parame ters, safety and tolerability, and a complete clinical chemistry program we re included in the study procedures. Results: Cerivastatin was well-tolerat ed and no serious adverse events were observed. In spite of the short treat ment period, treatment responses with respect to total cholesterol, LDL cho lesterol and triglycerides lowering were observed. Mean cerivastatin and me tabolite concentrations and thus systemic exposure were slightly higher (up to 50%) in patients on chronic dialysis compared to previous studies carri ed out in healthy subjects. The unbound fraction of cerivastatin ranged fro m 0.6 - 1.5% in these patients (normal range: 0.5 - 0.9%). The half-lives o f both parent drug (approximately 3 h) and metabolites remained unaffected and, most notably, no accumulation occurred under repeated dosing. In addit ion, cerivastatin clearance was not increased by concurrent dialysis as wou ld be predicted from the high plasma protein-binding (> 99%), and there wer e no significant differences in cerivastatin exposure between the dialysis period and the dialysis-free profile days. Conclusion: Cerivastatin can be safely administered in the usual dosages to patients with end-stage renal d isease 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 w ith caution.