Pharmacodynamics, safety, tolerability, and pharmacokinetics of the 0.8-mgdose of cerivastatin in patients with primary hypercholesterolemia

Cerivastatin is a third generation hydroxy-methyl-glutaryl-Co-enzyme A (HMG -CoA) reductase inhibitor proven to lower low-density lipoprotein (LDL) cho lesterol 28% to 31% in patients with primary hypercholesterolemia when give n at 0.3 mg/day. This study evaluates the safety, tolerability, pharmacodyn amics, and pharmocokinetics of cerivastatin 0.8 mg once daily for 4 weeks. In this randomized, double-blind, placebo-controlled parallel group trial c onducted at 2 study centers, 41 patients (63% women) with primary hyperchol esterolemia were placed on an American Heart Association Step 1 diet for 4 weeks. Single-blind placebo was administered for the final 2 weeks, before randomization. Patients received cerivastatin 0.8 mg (n = 28) or placebo (n = 13) once each evening for 28 days. Cerivastatin at 0.8 mg daily was well tolerated. No discontinuations occurred during the study. Adverse events w ere mild and transient. One cerivastatin-treated patient experienced asympt omatic creatinine kinase, 8 x the upper limit of normal (ULN) elevation on the last day of the study, which resolved 6 days after the completion of th e study. Cerivastatin 0.8 mg daily significantly reduced LDL cholesterol co mpared with placebo (-44.0 +/- 2.0% vs 2.2 +/- 2.8%, p <0.0001); total chol esterol (-30.8 +/- 1.4% vs 2.6 +/- 2,1%, p <0.0001), triglycerides (-11.2 /- 5.9% vs 15.9 +/- 8.6%, p < 0.02), but did not significantly alter high-d ensity lipoprotein (HDL) cholesterol (3.2 +/- 2.1% vs -1.2 +/- 3,1%, p = NS ). The pharmacokinetics of the 0.8-mg dose revealed dose proportional eleva tions in the 24-hour area under the curve and maximum plasma concentration relative to 0.3- and 0.4-mg doses with no change in time to maximum concent ration or the elimination half-life in plasma. The increased efficacy and l ack of clinically significant laboratory abnormalities or adverse events de monstrates a need for a large long-term study to confirm the safety and eff icacy of this dose of cerivastatin. (C) 1999 by Excerpta Medica, Inc.