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

Abstract

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.

Atorvastatin neutralises the thrombin-induced tissue factor expresion in endothelial cells via geranylgeranyl pyrophosphate

“…This effect was statistically significant for atorvastatin concentrations equal to or higher than 0.05 lM. The effect of atorvastatin was observed at concentrations that can be reached in circulating blood during chronic atorvastatin therapy (Cilla et al 1996), suggesting that the effect of atorvastatin observes in this study are clinically relevant. To confirm that the inhibitory effect of atorvastatin on thrombin-induced TF activity was due to deprivation of mevalonate, FPP or GGPP, HUVEC were incubated with either 100 lM mevalonate, or 5 lM FPP, or 5 lM GGPP in the presence of 1 lM atorvastatin for 24 h and then cells were stimulated with thrombin.…”

Induction of the Cytoprotective Enzyme Heme Oxygenase-1 by Statins Is Enhanced in Vascular Endothelium Exposed to Laminar Shear Stress and Impaired by Disturbed Flow

“…In contrast, exposure to OF, representing the atheroprone waveform revealed significant attenuation in shear stress-induced HO-1 expression, and no response to atorvastatin. Although exposure to LSS reduced the concentration of statin required to induce HO-1, we failed to demonstrate induction with 0.3 M atorvastatin, which is thought to be at the upper limit of the plasma concentration achieved therapeutically (40). This may reflect the lack of pulsatility in the LSS model, which is a limitation of our study.…”

Human Platelets Express Organic Anion-Transporting Peptide 2B1, an Uptake Transporter for Atorvastatin

“…We have chosen atorvastatin as a model statin for functional analysis because it has been described as a high-affinity substrate for OATP2B1 (Grube et al, 2006). In addition, it can achieve high systemic concentrations (Cilla et al, 1996). Maximum plasma concentrations occur over a range of 30 min to 6 h. The elimination half-life varies from 15 to 58 h, so atorvastatin can accumulate in blood (Lins et al, 2003), whereas most of the other statins have markedly shorter elimination half-lives.…”