MULTIPLE-DOSE PHARMACOKINETICS, PHARMACODYNAMICS, AND SAFETY OF ATORVASTATIN, AN INHIBITOR OF HMG-COA REDUCTASE, IN HEALTHY-SUBJECTS

This study examined the pharmacokinetics, pharmacodynamics, and safety of atorvastatin, an investigational inhibitor of 3-hydroxy-3-methylgl utaryl coenzyme A (HMG-CoA) reductase, in 50 healthy subjects by means of a randomized, double-blind parallel-group design. Volunteers recei ved rising single and multiple doses of 0.5 to 80 mg/day atorvastatin (40 subjects) or placebo (10 subjects). The drug was administered once or twice daily for 14 days. Atorvastatin was well tolerated by health y subjects. The most common adverse events reported after atorvastatin -headache and nausea-occurred as frequently after placebo. Atorvastati n peak concentration and area under the plasma concentration-time curv e (AUC) values increased more than proportionally with atorvastatin do se after both single and multiple drug doses. The extent of atorvastat in absorption (AUC) was similar after once- or twice-daily drug admini stration. Steady-state drug concentrations were achieved by the third day of drug dosing. Mean elimination half-life values ranged from 11 t o 24 hours. Atorvastatin accumulation was approximately 1.5- and %.0-f old after once- and twice-daily administration, respectively. Atorvast atin produced dose-related reductions in total cholesterol and low-den sity lipoprotein cholesterol that were similar after once- and twice-d aily drug administration. Reductions in mean total cholesterol and low -density lipoprotein cholesterol values ranged from 13% and 22% (2.5 m g/day) to 45% and 58% (80 mg/day), respectively (p less than or equal to 0.0013 in comparison with placebo and with baseline over this dose range). In summary, atorvastatin doses of up to 80 mg/day were well to lerated and had significant cholesterol-lowering effects.