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.
The effect of atovarstatin on digoxin pharmacokinetics was assessed in 24 healthy volunteers in two studies. Subjects received 0.25 mg digoxin daily for 20 days, administered alone for the first 10 days and concomitantly with 10 mg or 80 mg atorvastatin for the last 10 days. Mean steady-state plasma digoxin concentrations were unchanged by administration of 10 mg atorvastatin. Mean steady-state plasma digoxin concentrations following administration of digoxin with 80 mg atorvastatin were slightly higher than concentrations following administration of digoxin alone, resulting in 20% and 15% higher Cmax and AUC(0-24) values, respectively. Since tmax and renal clearance were not significantly affected, the results are consistent with an increase in the extent of digoxin absorption in the presence of atorvastatin. Digoxin is known to undergo intestinal secretion mediated by P-glycoprotein. Since atorvastatin is a CYP3A4 substrate and many CYP3A4 substrates are also substrates for P-glycoprotein transport, the influence of atorvastatin and its metabolites on P-glycoprotein-mediated digoxin transport in monolayers of the human colon carcinoma (Caco-2) cell line was investigated. In this model system, atorvastatin exhibited efflux or secretion kinetics with a K(m) of 110 microM. Atorvastatin (100 microM) inhibited digoxin secretion (transport from the basolateral to apical aspect of the monolayer) by 58%, equivalent to the extent of inhibition observed with verapamil, a known inhibitor of P-glycoprotein transport. Thus, the increase in steady-state digoxin concentrations produced by 80 mg atorvastatin coadministration may result from inhibition of digoxin secretion into the intestinal lumen.
Tolerance and pharmacokinetics after single-dose administration of atorvastatin, an investigational inhibitor of HMG-CoA reductase, were examined in 22 healthy volunteers in a three-period, partially-blinded study. 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 similar after administration of atorvastatin capsules and placebo. Atorvastatin solution was slightly less well tolerated. The most common side effect after administration of capsules and solution was headache, followed by sporadic reports of diarrhea, flatulence, and nausea. At the 120-mg solution dose, one participant experienced mild, transient restlessness, euphoria, and mental confusion that were considered to be dose-limiting side effects. Mean concentrations of atorvastatin, maximum concentration (Cmax), and area under the concentration-time curve from time 0 to the time of the last detectable concentration (AUCo-tldc) increased with increasing dose. Plasma elimination half-life (t1/2) ranged from 14.7 to 57.6 hours. The bioavailability of atorvastatin capsules was similar to that of solution. These results suggest that atorvastatin is well tolerated after single doses as high as 80 mg, and may require administration only once daily.
Atorvastatin is a new 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor that reduces plasma cholesterol by inhibiting cholesterol synthesis and increasing cellular uptake of low density lipoproteins. The effects of age and gender on the pharmacokinetics of atorvastatin after administration of single 20-mg tablets of atorvastatin were studied in 16 young and 16 elderly volunteers (8 men and 8 women in each age group). Plasma equivalent concentrations of atorvastatin were quantitated by a validated enzyme inhibition bioassay. Atorvastatin was well tolerated by the participants. The equivalent maximum concentration (Cmax) of atorvastatin was 42.5% higher in elderly participants (age, 66-92 years) than in young participants (age, 19-35 years) and 17.6% higher in women than in men. In addition, mean area under the concentration-time curve (AUC0-infinity) and half-life (t1/2) were 27.3% greater and 36.2% longer, respectively, in elderly adults than in young adults and 11.3% lower and 19.9% shorter, respectively, in women than in men. Because the primary site of action for HMG-CoA reductase inhibitors is the liver and atorvastatin is subject to extensive first-pass hepatic metabolism, it is unclear whether these age- and gender-related differences in the pharmacokinetics of atorvastatin will be clinically important. Results of subsequent safety and efficacy trials should help clarify the clinical significance of these pharmacokinetic differences.
The pharmacodynamic effects and pharmacokinetics of atorvastatin, a potent investigational inhibitor of HMG-CoA reductase, were studied in 16 normolipidemic subjects after administration of 40 mg daily for 15 days in the morning or evening. Lipid and apolipoprotein parameters were determined, and plasma atorvastatin equivalent concentrations were measured according to a validated enzyme inhibition bioassay procedure. Atorvastatin was well tolerated by the participants. Overall, mean reductions of 34% in total cholesterol, 48% in low-density lipoprotein (LDL) cholesterol, 37% in very low density lipoprotein (VLDL) cholesterol, 25% in triglycerides, 6% in apolipoprotein A-I, and 34% in apolipoprotein B were observed. Changes in lipid and apolipoprotein values were similar after morning and evening administration of atorvastatin. In contrast, studies with other HMG-CoA reductase inhibitors have consistently shown that evening administration results in larger reductions in total and LDL cholesterol than does morning administration. Rate and extent of equivalent absorption of atorvastatin were lower during evening than morning administration. Mean elimination half-life values were similar, however, suggesting that there is no diurnal variation in disposition of this drug. Pharmacokinetic differences did not correlate with effects on serum lipids.
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