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Tags: atorvastatin, atorvastatin calcium, calcium tablets, change from baseline, controlled trials, decreases, double blind studies, hmg coa reductase inhibitors, hypercholesterolemia, iia, ldl, lipitor, multicenter, percent change, ra, randomization, tg,Pages: 2
Language: english
Created: Wed Mar 1 15:49:14 2000
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In patients with Fredrickson Types IIa and IIb hyperlipoproteinemia pooled from 24 controlled trials, the median (25th
® and 75th percentile) percent changes from baseline in HDL-C for atorvastatin 10, 20, 40, and 80 mg were 6.4 (-1.4, 14),
Lipitor 8.7 (0, 17), 7.8 (0, 16), and 5.1 (-2.7, 15), respectively. Additionally, analysis of the pooled data demonstrated consistent
and significant decreases in total-C, LDL-C, TG, total-C/HDL-C, and LDL-C/HDL-C.
(Atorvastatin Calcium) Tablets In three multicenter, double-blind studies in patients with hypercholesterolemia, Lipitor was compared to other HMG-
CoA reductase inhibitors. After randomization, patients were treated for 16 weeks with either Lipitor 10 mg per day or a
fixed dose of the comparative agent (Table 2).
TABLE 2. Mean Percent Change From Baseline at End Point
(Double-Blind, Randomized, Active-Controlled Trials)
DESCRIPTION
Treatment Non-HDL-C/
Lipitor® (atorvastatin calcium) is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methyl- (Daily Dose) N Total-C LDL-C Apo B TG HDL-C HDL-C
glutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an
early and rate-limiting step in cholesterol biosynthesis. Study 1
Atorvastatin calcium is [R-(R*, R*)]-2-(4-fluorophenyl)- , -dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) Atorvastatin 10 mg 707 -27a -36a -28a -17a +7 -37a
bd
carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The empirical formula of atorvastatin calcium is Lovastatin 20 mg 191 -19 -27 -20 - 6 +7 -28
(C33H34FN2O5)2Ca·3H2O and its molecular weight is 1209.42. Its structural formula is: 95% CI for Diff1 -9.2, -6.5 -10.7, -7.1 -10.0, -6.5 -15.2, -7.1 -1.7, 2.0 -11.1, -7.1
Study 2
Atorvastatin 10 mg 222 -25b -35b -27b -17b +6 -36b
CH3 CH3
CH
Pravastatin 20 mg 77 -17 -23 -17 - 9 +8 -28
O OH OH O
95% CI for Diff1 -10.8, -6.1 -14.5, -8.2 -13.4, -7.4 -14.1, -0.7 -4.9, 1.6 -11.5, -4.1
NHC CH2 CH CH C
N CH2 CH2 CH2 O Study 3
+
· Ca2 Atorvastatin 10 mg 132 -29c -37c -34c -23c +7 -39c
· 3H2O Simvastatin 10 mg 45 -24 -30 -30 -15 +7 -33
F 95% CI for Diff1 -8.7, -2.7 -10.1, -2.6 -8.0, -1.1 -15.1, -0.7 -4.3, 3.9 -9.6, -1.9
1 A negative value for the 95% Cl for the difference between treatments favors atorvastatin for all except HDL-C, for which a positive value favors
atorvastatin. If the range does not include 0, this indicates a statistically significant difference.
a
2 Significantly different from lovastatin, ANCOVA, p 0.05
b
Significantly different from pravastatin, ANCOVA, p 0.05
c
Atorvastatin calcium is a white to off-white crystalline powder that is insoluble in aqueous solutions of pH 4 and Significantly different from simvastatin, ANCOVA, p 0.05
below. Atorvastatin calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile, slightly The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown in Table 2 is not
soluble in ethanol, and freely soluble in methanol. known. Table 2 does not contain data comparing the effects of atorvastatin 10 mg and higher doses of lovastatin,
Lipitor tablets for oral administration contain 10, 20, or 40 mg atorvastatin and the following inactive ingredients: cal- pravastatin, and simvastatin. The drugs compared in the studies summarized in the table are not necessarily inter-
cium carbonate, USP; candelilla wax, FCC; croscarmellose sodium, NF; hydroxypropyl cellulose, NF; lactose monohy- changeable.
drate, NF; magnesium stearate, NF; microcrystalline cellulose, NF; Opadry White YS-1-7040 (hydroxypropylmethyl- In a large clinical study, the number of patients meeting their National Cholesterol Education Program-Adult Treatment
cellulose, polyethylene glycol, talc, titanium dioxide); polysorbate 80, NF; simethicone emulsion. Panel (NCEP-ATP) II target LDL-C levels on 10 mg of Lipitor daily was assessed. After 16 weeks, 156/167 (93%) of
CLINICAL PHARMACOLOGY patients with less than 2 risk factors for CHD and baseline LDL-C 190 mg/dL reached a target of 160 mg/dL; 141/218
(65%) of patients with 2 or more risk factors for CHD and LDL-C 160 mg/dL achieved a level of 130 mg/dL LDL-C; and
Mechanism of Action
21/113 (19%) of patients with CHD and LDL-C 130 mg/dL reached a target level of 100 mg/dL LDL-C.
Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-
hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Cholesterol and Hypertriglyceridemia (Fredrickson Type IV)
triglycerides circulate in the bloodstream as part of lipoprotein complexes. With ultracentrifugation, these complexes The response to Lipitor in 64 patients with isolated hypertriglyceridemia treated across several clinical trials is shown in
separate into HDL (high-density lipoprotein), IDL (intermediate-density lipoprotein), LDL (low-density lipoprotein), the table below. For the atorvastatin-treated patients, median (min, max) baseline TG level was 565 (267-1502).
and VLDL (very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol in the liver are incorporated into
VLDL and released into the plasma for delivery to peripheral tissues. LDL is formed from VLDL and is catabolized pri- TABLE 3. Combined Patients With Isolated Elevated TG:
marily through the high-affinity LDL receptor. Clinical and pathologic studies show that elevated plasma levels of total Median (min, max) Percent Changes From Baseline
cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis and are
risk factors for developing cardiovascular disease, while increased levels of HDL-C are associated with a decreased Placebo Atorvastatin 10 mg Atorvastatin 20 mg Atorvastatin 80 mg
cardiovascular risk. (N=12) (N=37) (N=13) (N=14)
In animal models, Lipitor lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and
cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell-surface to Triglycerides -12.4 (-36.6, 82.7) -41.0 (-76.2, 49.4) -38.7 (-62.7, 29.5) -51.8 (-82.8, 41.3)
enhance uptake and catabolism of LDL; Lipitor also reduces LDL production and the number of LDL particles. Lipitor Total-C -2.3 (-15.5, 24.4) -28.2 (-44.9, -6.8) -34.9 (-49.6, -15.2) -44.4 (-63.5, -3.8)
reduces LDL-C in some patients with homozygous familial hypercholesterolemia (FH), a population that rarely
responds to other lipid-lowering medication(s). LDL-C 3.6 (-31.3, 31.6) -26.5 (-57.7, 9.8) -30.4 (-53.9, 0.3) -40.5 (-60.6, -13.8)
A variety of clinical studies have demonstrated that elevated levels of total-C, LDL-C, and apo B (a membrane complex
for LDL-C) promote human atherosclerosis. Similarly, decreased levels of HDL-C (and its transport complex, apo A) HDL-C 3.8 (-18.6, 13.4) 13.8 (-9.7, 61.5) 11.0 (-3.2, 25.2) 7.5 (-10.8, 37.2)
are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovas-
cular morbidity and mortality vary directly with the level of total-C and LDL-C, and inversely with the level of HDL-C. VLDL-C -1.0 (-31.9, 53.2) -48.8 (-85.8, 57.3) -44.6 (-62.2, -10.8) -62.0 (-88.2, 37.6)
Lipitor reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous FH, nonfamilial forms of
hypercholesterolemia, and mixed dyslipidemia. Lipitor also reduces VLDL-C and TG and produces variable increases non-HDL-C -2.8 (-17.6, 30.0) -33.0 (-52.1, -13.3) -42.7 (-53.7, -17.4) -51.5 (-72.9, -4.3)
in HDL-C and apolipoprotein A-1. Lipitor reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and increases
HDL-C in patients with isolated hypertriglyceridemia. Lipitor reduces intermediate density lipoprotein cholesterol Dysbetalipoproteinemia (Fredrickson Type III)
(IDL-C) in patients with dysbetalipoproteinemia. The effect of Lipitor on cardiovascular morbidity and mortality has The results of an open-label crossover study of 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with dysbeta-
not been determined. lipoproteinemia (Fredrickson Type III) are shown in the table below.
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate density lipoprotein (IDL),
TABLE 4. Open-Label Crossover Study of 16 Patients
and remnants, can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low
With Dysbetalipoproteinemia (Fredrickson Type III)
HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart
disease. As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Median % Change (min, max)
Furthermore, the independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular mor-
bidity and mortality has not been determined. Median (min, max) at Atorvastatin 10 mg Atorvastatin 80 mg
Baseline (mg/dL)
Pharmacodynamics
Atorvastatin as well as some of its metabolites are pharmacologically active in humans. The liver is the primary site of Total-C 442 (225, 1320) -37 (-85, 17) -58 (-90, -31)
action and the principal site of cholesterol synthesis and LDL clearance. Drug dosage rather than systemic drug con- Triglycerides 678 (273, 5990) -39 (-92, -8) -53 (-95, -30)
centration correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic
response (see DOSAGE AND ADMINISTRATION). IDL-C + VLDL-C 215 (111, 613) -32 (-76, 9) -63 (-90, -8)
Pharmacokinetics and Drug Metabolism non-HDL-C 411 (218, 1272) -43 (-87, -19) -64 (-92, -36)
Absorption: Atorvastatin is rapidly absorbed after oral administration; maximum plasma concentrations occur within
1 to 2 hours. Extent of absorption increases in proportion to atorvastatin dose. The absolute bioavailability of atorva- Homozygous Familial Hypercholesterolemia
statin (parent drug) is approximately 14% 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 In a study without a concurrent control group, 29 patients ages 6 to 37 years with homozygous FH received maximum
and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approxi- daily doses of 20 to 80 mg of Lipitor. The mean LDL-C reduction in this study was 18%. Twenty-five patients with a
mately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether atorvastatin is reduction in LDL-C had a mean response of 20% (range of 7% to 53%, median of 24%); the remaining 4 patients had
given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) fol- 7% to 24% increases in LDL-C. Five of the 29 patients had absent LDL-receptor function. Of these, 2 patients also had a
lowing evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the portacaval shunt and had no significant reduction in LDL-C. The remaining 3 receptor-negative patients had a mean
time of day of drug administration (see DOSAGE AND ADMINISTRATION). LDL-C reduction of 22%.
Distribution: Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is 98% bound to INDICATIONS AND USAGE
plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Lipitor is indicated:
Based on observations in rats, atorvastatin is likely to be secreted in human milk (see CONTRAINDICATIONS,
Pregnancy and Lactation, and PRECAUTIONS, Nursing Mothers). 1. as an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in patients with
primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa
Metabolism: Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxi-
and IIb);
dation products. 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 2. as an adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson Type IV);
metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent
3. for the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond ade-
with increased plasma concentrations of atorvastatin in humans following coadministration with erythromycin, a
quately to diet;
known inhibitor of this isozyme (see PRECAUTIONS, Drug Interactions). In animals, the ortho-hydroxy metabolite
undergoes further glucuronidation. 4. to reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-
Excretion: Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extrahepatic lowering treatments (eg, LDL apheresis) or if such treatments are unavailable.
metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination Therapy with lipid-altering agents should be a component of multiple-risk-factor intervention in individuals at increased
half-life of atorvastatin in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA risk for atherosclerotic vascular disease due to hypercholesterolemia. Lipid-altering agents should be used in addition to
reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is a diet restricted in saturated fat and cholesterol only when the response to diet and other nonpharmacological measures
recovered in urine following oral administration. has been inadequate (see National Cholesterol Education Program (NCEP) Guidelines, summarized in Table 5).
Special Populations
TABLE 5. NCEP Guidelines for Lipid Management
Geriatric: Plasma concentrations of atorvastatin are higher (approximately 40% for Cmax and 30% for AUC) in Definite LDL-Cholesterol
healthy elderly subjects (age 65 years) than in young adults. LDL-C reduction is comparable to that seen in younger Atherosclerotic Two or More Other mg/dL (mmol/L)
patient populations given equal doses of Lipitor.
Diseasea Risk Factorsb Initiation Minimum
Pediatric: Pharmacokinetic data in the pediatric population are not available. Level Goal
Gender: Plasma concentrations of atorvastatin in women differ from those in men (approximately 20% higher for No No 190