Multiple-dose pharmacokinetics, pharmacodynamics, and safety of atorvastatin, an inhibitor of HMG-CoA reductase, in healthy subjects

• Published in: Clinical pharmacology and therapeutics Vol. 60; no. 6; p. 687
• Main Authors: Cilla, Jr, D D, Whitfield, L R, Gibson, D M, Sedman, A J, Posvar, E L
• Format: Journal Article
• Language: English
• Published: United States 01-12-1996
• Subjects: Acyl Coenzyme A - antagonists & inhibitors; Adult; Anticholesteremic Agents - administration & dosage; Anticholesteremic Agents - adverse effects; Anticholesteremic Agents - pharmacokinetics; Anticholesteremic Agents - pharmacology; Area Under Curve; Atorvastatin Calcium; Cholesterol - blood; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Female; Half-Life; Heptanoic Acids - administration & dosage; Heptanoic Acids - adverse effects; Heptanoic Acids - pharmacokinetics; Heptanoic Acids - pharmacology; Humans; Least-Squares Analysis; Linear Models; Male; Middle Aged; Pyrroles - administration & dosage; Pyrroles - adverse effects; Pyrroles - pharmacokinetics; Pyrroles - pharmacology; Reference Values
• DOI: 10.1016/S0009-9236(96)90218-0
• ISSN: 0009-9236

This study examined the pharmacokinetics, pharmacodynamics, and safety of atorvastatin, an investigational inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, in 50 healthy subjects by means of a randomized, double-blind parallel-group design. Volunteers received 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 healthy subjects. The most common adverse events reported after atorvastatin-headache and nausea-occurred as frequently after placebo. Atorvastatin peak concentration and area under the plasma concentration-time curve (AUC) values increased more than proportionally with atorvastatin dose after both single and multiple drug doses. The extent of atorvastatin absorption (AUC) was similar after once- or twice-daily drug administration. Steady-state drug concentrations were achieved by the third day of drug dosing. Mean elimination half-life values ranged from 11 to 24 hours. Atorvastatin accumulation was approximately 1.5- and 3.0-fold after once- and twice-daily administration, respectively. Atorvastatin produced dose-related reductions in total cholesterol and low-density lipoprotein cholesterol that were similar after once- and twice-daily drug administration. Reductions in mean total cholesterol and low-density lipoprotein cholesterol values ranged from 13% and 22% (2.5 mg/day) to 45% and 58% (80 mg/day), respectively (p < or = 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 tolerated and had significant cholesterol-lowering effects.