Sign Out
Pharmacology: Pharmacodynamics: Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) to mevalonate, a precursor of sterols, including cholesterol. Triglycerides (TG) and cholesterol in the liver are incorporated into very low-density lipoproteins (VLDL) and released into the plasma for delivery to peripheral tissues. Low density lipoprotein (LDL) is formed from VLDL and is catabolized primarily through the receptor with high affinity to LDL (LDL receptor).
Atorvastatin lowers plasma cholesterol and lipoprotein serum concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver and increases the number of hepatic LDL receptors on the cell surface for enhanced uptake and catabolism of LDL.
Atorvastatin reduces LDL production and the number of LDL particles. Atorvastatin produces a profound and sustained increase in LDL receptor activity coupled with a beneficial change in the quality of circulating LDL particles. Atorvastatin is effective in reducing LDL-C in patients with homozygous familial hypercholesterolemia, a population that has not usually responded to lipid lowering medication.
Atorvastatin has been shown to reduce concentrations of total-C (TC) (30-46%), LDL-C (41-61%), apolipoprotein B (34-50%) and triglycerides (14-33%) while producing variable increases in high density lipoprotein (HDL)-C and apolipoprotein A1 in a dose response study.
These results are consistent in patients with heterozygous familial hypercholesterolemia, nonfamilial forms of hypercholesterolemia and mixed hyperlipidemia, including patients with noninsulin-dependent diabetes mellitus.
Reductions in total-C, LDL-C and apolipoprotein B have been proven to reduce risk for cardiovascular events and mortality.
Atherosclerosis: In the reversing atherosclerosis with aggressive lipid-lowering study (REVERSAL), the effect of intensive lipid-lowering with atorvastatin 80 mg and standard degree of lipid-lowering with pravastatin 40 mg on coronary atherosclerosis was assessed by intravascular ultrasound (IVUS), during angiography, in patients with coronary heart disease (CHD). In this randomized, double-blind, multicenter-controlled clinical trial, IVUS was performed at baseline and at 18 months in 502 patients. In the atorvastatin group (n=253), there was no progression of atherosclerosis.
The median percent change, from baseline, in total atheroma volume (the primary study criteria) was -0.4% (p=0.98) in the atorvastatin group and +2.7% (p=0.001) in the pravastatin group (n=249). When compared to pravastatin, the effects of atorvastatin were statistically significant (p=0.02). The effect of intensive lipid-lowering with atorvastatin on cardiovascular coronary death was not investigated in this study. Therefore, the clinical significance of these imaging results with regard to the primary and secondary prevention of cardiovascular events is unknown.
In the atorvastatin group, LDL-C was reduced to a mean of 2.04 mmol/L±0.8 (78.9 mg/dL±30) from baseline 3.89 mmol/L±0.7 (150 mg/dL±28) and in the pravastatin group, LDL-C was reduced to a mean of 2.85 mmol/L±0.7 (110 mg/dL±26) from baseline 3.89 mmol/L±0.7 (150 mg/dL±26) (p<0.0001). Atorvastatin also significantly reduced mean TC by 34.1% (pravastatin: -18.4%, p<0.0001), mean TG levels by 20% (pravastatin: -6.8%, p<0.0009) and mean apolipoprotein B by 39.1% (pravastatin: -22%, p<0.0001). Atorvastatin increased mean HDL-C by 2.9% (pravastatin: +5.6%, p=NS). There was a 36.4% mean reduction in CRP in the atorvastatin group compared to a 5.2% reduction in the pravastatin group (p<0.0001).
Study results were obtained with the 80 mg dose strength. Therefore, they cannot be extrapolated to the lower dose strengths.
The safety and tolerability profiles of the 2 treatment groups were comparable.
Heterozygous Familial Hypercholesterolemia in Pediatric Patients: In a double-blind, placebo-controlled study followed by an open-label phase, 187 boys and postmenarchal girls 10-17 years (mean age 14.1 years) with heterozygous familial hypercholesterolemia (FH) or severe hypercholesterolemia were randomized to atorvastatin (n=140) or placebo (n=47) for 26 weeks and then all received atorvastatin for 26 weeks. Inclusion in the study required: (1) a baseline LDL-C level 34.91 mmol/L or (2) a baseline LDL-C 34.14 mmol/L and positive family history of FH or documented premature cardiovascular disease in a 1st- or 2nd-degree relative. The mean baseline LDL-C value was 5.65 mmol/L (range: 3.58-9.96 mmol/L) in the atorvastatin group compared to 5.95 mmol/L (range: 4.14-8.39 mmol/L) in placebo group. The dosage of atorvastatin (once daily) was 10 mg for the first 4 weeks and up-titrated to 20 mg if the LDL-C level was >3.36 mmol/L. The number of atorvastatin-treated patients who required up-titration to 20 mg after week 4 during the double-blind phase was 80 (57.1%).
Atorvastatin significantly decreased plasma levels of total-C, LDL-C, triglycerides and apolipoprotein B (Apo) during the 26 week double-blind phase. (See Table 1.)
Click on icon to see table/diagram/imageThe mean achieved LDL-C value was 3.38 mmol/L (range: 1.81-6.26 mmol/L) in the atorvastatin group compared to 5.91 mmol/L (range: 3.93-9.96 mmol/L) in the placebo group during the 26-week double-blind phase.
In this limited controlled study, there was no detectable effect on growth or sexual maturation in boys or on menstrual length in girls. Atorvastatin has not been studied in controlled clinical trials involving pre-pubertal patients or patients <10 years. The safety and efficacy of doses >20 mg have not been studied in controlled trials in children. The long-term efficacy of atorvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
Prevention of Cardiovascular Disease: The effect of atorvastatin on fatal and nonfatal CHD was assessed in a randomized, double-blind, placebo-controlled study, the Anglo-Scandinavian cardiac outcomes trial lipid-lowering arm (ASCOT-LLA). Patients were hypertensive, 40-79 years, with no previous myocardial infarction or treatment for angina, and with TC levels ≤6.5 mmol/L (251 mg/dL). All patients had at least 3 of the predefined cardiovascular risk factors: Male gender, ≥55 years, smoking, diabetes, history of CHD in a 1st-degree relative, TC: HDL-C >6, peripheral vascular disease, left ventricular hypertrophy, prior cerebrovascular event, specific electrocardiogram (ECG) abnormality, proteinuria/albuminuria. Not all included patients were estimated to have a high risk for a 1st cardiovascular event.
Patients were treated with antihypertensive therapy (either amlodipine or atenolol-based regimen) and either atorvastatin 10 mg daily (n=5,168) or placebo (n=5,137).
The absolute and relative risk reduction effect of atorvastatin was as follows: See Table 2.
Click on icon to see table/diagram/imageTotal mortality and cardiovascular mortality were not significantly reduced (185 vs 212 events, p=0.17 and 74 vs 82 events, p=0.51). In the subgroup analyses by gender (81% males, 19% females), a beneficial effect of atorvastatin was seen in males but could not be established in females possibly due to the low event rate in the female subgroup. Overall and cardiovascular mortality were numerically higher in the female patients (38 vs 30 and 17 vs 12), but this was not statistically significant. There was significant treatment interaction by antihypertensive baseline therapy. The primary endpoint (fatal CHD plus nonfatal MI) was significantly reduced by atorvastatin in patients treated with amlodipine [Hazard Ratio (HR) 0.47 (0.32-0.69), p=0.00008], but not in those treated with atenolol [HR 0.83 (0.59-1.17), p=0.287].
The effect of atorvastatin on fatal and nonfatal cardiovascular disease was also assessed in a randomized, double-blind, multicenter, placebo-controlled trial, the collaborative atorvastatin diabetes study (CARDS) in patients with type 2 diabetes, 40-75 years, without prior history of cardiovascular disease, and with LDL-C ≤4.14 mmol/L (160 mg/dL) and TG ≤6.78 mmol/L (600 mg/dL).
All patients had at least 1 of the following risk factors: Hypertension, current smoking, retinopathy, microalbuminuria or macroalbuminuria.
Patients were treated with either atorvastatin 10 mg daily (n=1,428) or placebo (n=1,410) for a median follow-up of 3.9 years.
The absolute and relative risk reduction effect of atorvastatin was as follows: See Table 3.
Click on icon to see table/diagram/imageThere was no evidence of a difference in the treatment effect by patient's gender, age or baseline LDL-C level. A favorable trend was observed regarding the mortality rate (82 deaths in the placebo group vs 61 deaths in the atorvastatin group, p=0.0592).
Recurrent Stroke: In the stroke prevention by aggressive reduction in cholesterol levels (SPARCL) study, the effect of atorvastatin 80 mg daily or placebo on stroke was evaluated in 4,731 patients who had a stroke or transient ischemic attack (TIA) within the preceding 6 months and no history of a CHD. Patients were male 60%, 21-92 years (average age 63 years) and had an average baseline LDL of 133 mg/dL (3.4 mmol/L). The mean LDL-C was 73 mg/dL (1.9 mmol/L) during treatment with atorvastatin and 129 mg/dL (3.3 mmol/L) during treatment with placebo. Median follow-up was 4.9 years.
Atorvastatin 80 mg reduced the risk of the primary endpoint of fatal or nonfatal stroke by 15% (HR 0.85; 95% CI, 0.72-1; p=0.05 or 0.84; 95% CI, 0.71-0.99; p=0.03 after adjustment for baseline factors) compared to placebo. All cause mortality was 9.1% (216/2,365) for atorvastatin versus 8.9% (211/2,366) for placebo.
In a post analysis, atorvastatin 80 mg reduced the incidence of ischemic stroke (218/2,365, 9.2% vs 274/2,366, 11.6%, p=0.01) and increased the incidence of hemorrhagic stroke (55/2,365, 2.3% vs 33/2,366, 1.4%, p=0.02) compared to placebo.
The risk of hemorrhagic stroke was increased in patients who entered the study with prior hemorrhagic stroke (7/45 for atorvastatin vs 2/48 for placebo; HR 4.06; 95% CI, 0.84-19.57) and the risk of ischemic stroke was similar between groups (3/45 for atorvastatin vs 2/48 for placebo; HR 1.64; 95% CI, 0.27-9.82).
The risk of hemorrhagic stroke was increased in patients who entered the study with prior lacunar infarct (20/708 for atorvastatin vs 4/701 for placebo; HR 4.99; 95% CI, 1.71-14.61), but the risk of ischemic stroke was also decreased in these patients (79/708 for atorvastatin vs 102/701 for placebo; HR 0.76; 95% CI, 0.57-1.02). It is possible that the net risk of stroke is increased in patients with prior lacunar infarct who receive atorvastatin 80 mg/day.
All cause mortality was 15.6% (7/45) for atorvastatin versus 10/4% (5/48) in the subgroup of patients with prior hemorrhagic stroke. All cause mortality was 10.9% (77/708) for atorvastatin versus 9.1% (64/701) for placebo in the subgroup of patients with prior lacunar infarct.
Pharmacokinetics: Absorption: Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations (Cmax) occur within 1-2 hrs. Extent of absorption increases in proportion to atorvastatin dose. After oral administration, atorvastatin film-coated tablets are 95-99% bioavailable compared to the oral solution. The absolute bioavailability of atorvastatin is approximately 12% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism.
Distribution: Mean volume of distribution of atorvastatin is approximately 381 L. Atorvastatin is ≥98% bound to plasma proteins.
Metabolism: Atorvastatin is metabolized by cytochrome P450 (CYP450) 3A4 to ortho- and parahydroxylated derivatives and various β-oxidation products. Apart from other pathways these products are further metabolized via glucuronidation. In vitro, inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites.
Excretion: Atorvastatin is eliminated primarily in bile following hepatic and/or extrahepatic metabolism.
However, Avamax does not appear to undergo significant enterohepatic recirculation. Mean plasma elimination half-life (t½) of atorvastatin in humans is approximately 14 hrs. The t½ of inhibitory activity for HMG-CoA reductase is approximately 20-30 hrs due to the contribution of active metabolites.
Special Populations: Geriatric: Plasma concentrations of atorvastatin and its active metabolites are higher in healthy elderly subjects than in young adults while the lipid effects were comparable to those seen in younger patient populations.
Pediatric: Pharmacokinetic data in the pediatric population are not available.
Gender: Concentrations of atorvastatin and its active metabolites in women differ from those in men [Women: approximately 20% higher for Cmax and approximately 10% lower for area under the curve (AUC)]. These differences were of no clinical significance, resulting in no clinically significant differences in lipid effects among men and women.
Renal Insufficiency: Renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin and its active metabolites.
Hepatic Insufficiency: Plasma concentrations of atorvastatin and its active metabolites are markedly increased (approximately 16-fold in Cmax and approximately 11-fold in AUC) in patients with chronic alcoholic liver disease (Childs-Pugh B).
Toxicology: Preclinical Safety Data: Atorvastatin was not carcinogenic in rats. The maximum dose used was 63-fold higher than the highest human dose (80 mg/day) on a mg/kg body-weight basis and 8- to 16-fold higher based on AUC(0-24 hr) values as determined by total inhibitory activity. In a 2-year study in mice, incidences of hepatocellular adenoma in males and hepatocellular carcinomas in females were increased at the maximum dose used, and the maximum dose used was 250-fold higher than the highest human dose on a mg/kg body-weight basis. Systemic exposure was 6- to 11-fold higher based on AUC(0-24 hr). Atorvastatin did not demonstrate mutagenic or clastogenic potential in 4 in vitro tests with and without metabolic activation and in 1 in vivo assay. In animal studies, atorvastatin had no effect on male or female fertility at doses up to 175 mg/kg/day and 225 mg/kg/day, respectively and was not teratogenic.
