Influence of renal function on the pharmacokinetics of cerivastatin in normocholesterolemic adults

Objective: The influence of impaired renal function on the pharmacokinetics of single and multiple doses of cerivastatin was evaluated in this nonrand omized, non-blinded, 7-day, multiple-dose study. Methods: Thirty-five adults between the ages of 21 years and 75 years with normal renal function (CLCR >90 ml/min/1.73 m(2), n = 9), or patients with either mild (CLCR 61 ml/min/1.73 m(2) to less than or equal to 90 ml.min/1. 73 m(2), n = 9), moderate (CLCR 30 ml/min/1.73 m(2) to less than or equal t o 60 ml/min/1.73 m(2), n = 8), or severe (CLCR <30 ml/min/1.73 m(2), but no t on dialysis, n = 9) renal impairment were given cerivastatin 0.3 mg daily each evening for 7 days. The steady-state pharmacokinetics of cerivastatin , including the area under the concentration-time curve (AUC)(0-24), peak p lasma concentration (C-max), time to reach C-max (t(max)) and elimination h alf-life (t(1/2)) were determined on day 1 and day 7. The logarithm of the pharmacokinetic variables was analyzed using analysis of variance (ANOVA). Safety assessments included physical examination, fundoscopy, vital signs, electrocardiogram (ECG), adverse events, and laboratory safety indices. Results: The day-1 AUC in patients with mild renal impairment was similar t o that of patients with normal function (19.6 mu g/h/l vs 19.2 mu g/h/l, re spectively). However, the AUC for cerivastatin patients with moderate or se vere renal impairment was 40-60% higher (30.8 mu g/h/l and 29.0 mu g/h/l, r espectively). C-max values for patients with normal, mild, moderate, and se vere renal impairment were 3.3, 3.4, 4.6, and 5.2 mu g/l, respectively. Thi s modest increase in plasma cerivastatin levels is nearly equivalent to a 0 .4-mg daily dose, which has been recently approved in the United States. Th e mean t(1/2) of cerivastatin was less than 4.5 h in all patients, indicati ng that renal dysfunction did not promote cerivastatin accumulation. This o bservation was confirmed by the finding that the cerivastatin plasma levels on day 1 and day 7 were similar in all patient groups. Furthermore, the me an AUC and C-max values for both demethylated and hydroxylated cerivastatin were similar in the patients with the most severe renal dysfunction to the corresponding values in healthy subjects. Cerivastatin was well tolerated in all patients irrespective of renal function. Adverse events were observe d in 37% of the subjects nearly all were mild and generally of short durati on, and most resolved without intervention. Incidence of adverse events was similar across all three renal groups and the control group. There were no clinically significant laboratory changes other than those consistent with renal disease. Conclusion: This study demonstrates that dosage adjustment of the daily 0.3 -mg cerivastatin dose in patients with significant renal impairment is like ly unnecessary.