Mechanism of Action
LIPITOR 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 triglycerides circulate in the
bloodstream as part of lipoprotein complexes. With ultracentrifugation, these complexes
separate into HDL (high-density lipoprotein), IDL (intermediate-density lipoprotein),
LDL (low-density lipoprotein), 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 primarily through the high-affinity LDL receptor. Clinical and pathologic
studies show that elevated plasma levels of total 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 cardiovascular risk.
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 enhance uptake and catabolism of
LDL; LIPITOR also reduces LDL production and the number of LDL particles. LIPITOR
reduces LDL-C in some patients with homozygous familial hypercholesterolemia (FH),
a population that rarely responds to other lipid-lowering medication(s).
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) are associated with
the development of atherosclerosis. Epidemiologic investigations have established
that cardiovascular morbidity and mortality vary directly with the level of total-C
and LDL-C, and inversely with the level of HDL-C.
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 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
(IDL-C) in patients with dysbetalipoproteinemia.
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate
density lipoprotein (IDL), and remnants, can also promote atherosclerosis. Elevated
plasma triglycerides are frequently found in a triad with low 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. Furthermore, the independent effect of
raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity
and mortality has not been determined.
Pharmacodynamics
LIPITOR, as well as some of its metabolites, are pharmacologically active in
humans. The liver is the primary site of action and the principal site of cholesterol
synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration,
correlates better with LDL-C reduction. Individualization of drug dosage should
be based on therapeutic response [see Dosage and Administration].
Pharmacokinetics
Absorption: LIPITOR is rapidly absorbed after oral administration; maximum
plasma concentrations occur within 1 to 2 hours. Extent of absorption increases
in proportion to LIPITOR dose. The absolute bioavailability of atorvastatin
(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 and/or hepatic first-pass metabolism.
Although food decreases the rate and extent of drug absorption by approximately
25% and 9%, respectively, as assessed by Cmax and AUC,
LDL-C reduction is similar whether LIPITOR is given with or without food. Plasma
LIPITOR concentrations are lower (approximately 30% for Cmax
and AUC) following evening drug administration compared with morning. However, LDL-C
reduction is the same regardless of the time of day of drug administration [see
Dosage and Administration].
Distribution: Mean volume of distribution of LIPITOR is approximately
381 liters. LIPITOR is ≥98% bound to plasma proteins. A blood/plasma ratio
of approximately 0.25 indicates poor drug penetration into red blood cells. Based
on observations in rats, LIPITOR is likely to be secreted in human milk [see
Contraindications, Nursing Mothers and Use in Specific Populations, Nursing Mothers].
Metabolism: LIPITOR is extensively metabolized to ortho- and parahydroxylated
derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA
reductase by ortho- and parahydroxylated metabolites is equivalent to that of LIPITOR.
Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed
to active metabolites. In vitro studies suggest the importance of LIPITOR
metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations
of LIPITOR in humans following co-administration with erythromycin, a known
inhibitor of this isozyme [see Drug Interactions]. In animals, the
ortho-hydroxy metabolite undergoes further glucuronidation.
Excretion: LIPITOR and its metabolites are eliminated primarily in bile
following hepatic and/or extra-hepatic metabolism; however, the drug does not appear
to undergo enterohepatic recirculation. Mean plasma elimination half-life of LIPITOR
in humans is approximately 14 hours, but the half-life of inhibitory activity for
HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites.
Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.
Specific Populations
Geriatric: Plasma concentrations of LIPITOR are higher (approximately
40% for Cmax and 30% for AUC) in healthy elderly subjects
(age ≥65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering
at any dose of drug in the elderly patient population compared to younger adults
[see Use in Specific Populations, Geriatric Use].
Pediatric: Pharmacokinetic data in the pediatric population are not available.
Gender: Plasma concentrations of LIPITOR in women differ from those
in men (approximately 20% higher for Cmax and 10% lower
for AUC); however, there is no clinically significant difference in LDL-C reduction
with LIPITOR between men and women.
Renal Impairment: Renal disease has no influence on the plasma concentrations
or LDL-C reduction of LIPITOR; thus, dose adjustment in patients with renal
dysfunction is not necessary [see Dosage and Administration, Dosage in Patients with Renal Impairmant, Warnings and Precautions, Skeletal Muscle].
Hemodialysis: While studies have not been conducted in patients with end-stage
renal disease, hemodialysis is not expected to significantly enhance clearance of
LIPITOR since the drug is extensively bound to plasma proteins.
Hepatic Impairment: In patients with chronic alcoholic liver disease,
plasma concentrations of LIPITOR are markedly increased. Cmax and AUC are each
4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and
11-fold increased, respectively, in patients
with Childs-Pugh B disease [see Contraindications].
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in
high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a
plasma AUC (0-24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose.
A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant increase in liver adenomas in
high-dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC (0–24) values of approximately
6 times the mean human plasma drug exposure after an 80 mg oral dose.
In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation:
the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese
hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test.
Studies in rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was
aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3 months
(16 times the human AUC at the 80 mg dose); testis weights were significantly lower at 30 and 100 mg/kg and epididymal weight
was lower at 100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid
head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or
reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for two years.