TOLERANCE AND PHARMACOKINETICS OF SINGLE-DOSE ATORVASTATIN, A POTENT INHIBITOR OF HMG-COA REDUCTASE, IN HEALTHY-SUBJECTS

Tolerance and pharmacokinetics after single-dose administration of ato rvastatin, an investigational inhibitor of HMG-CoA reductase, were exa mined in 22 healthy volunteers in a three-period, partially-blinded st udy. Participants received capsule and solution doses of atorvastatin (0.5 to 120 mg) and placebo at weekly intervals. Atorvastatin was well tolerated at doses as high as 80 mg. The adverse event profile was si milar after administration of atorvastatin capsules and placebo. Atorv astatin solution was slightly less well tolerated. The most common sid e effect after administration of capsules and solution was headache, f ollowed by sporadic reports of diarrhea, flatulence, and nausea. At th e 120-mg solution dose, one participant experienced mild, transient re stlessness, euphoria, and mental confusion that were considered to be dose-limiting side effects, Mean concentrations of atorvastatin, maxim um concentration (C-max), and area under the concentration-time curve from time 0 to the time of the last detectable concentration (AUC(0-tl dc)) increased with increasing dose. Plasma elimination half-life (t(1 /2)) ranged from 14.7 to 57.6 hours. The bioavailability of atorvastat in capsules was similar to that of solution, These results suggest tha t atorvastatin is well tolerated after single doses as high as 80 mg, and map require administration only once daily.