Lipitor (Atorvastatin Calcium) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

MECHANISM OF ACTION

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 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

Atorvastatin 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 AND DRUG METABOLISM

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 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 atorvastatin is given with or without food. Plasma atorvastatin 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 atorvastatin is approximately 381 liters. Atorvastatin 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, atorvastatin is likely to be secreted in human milk (see CONTRAINDICATIONS, Pregnancy and Lactation, and PRECAUTIONS, Nursing Mothers).

Metabolism: Atorvastatin 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 atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following coadministration with erythromycin, a known inhibitor of this isozyme (see PRECAUTIONS, Drug Interactions). In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.

Excretion: Atorvastatin 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 atorvastatin 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.

SPECIAL POPULATIONS

Geriatric: Plasma concentrations of atorvastatin 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 PRECAUTIONS section; Geriatric Use subsection).

Pediatric: Pharmacokinetic data in the pediatric population are not available.

Gender: Plasma concentrations of atorvastatin 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 Insufficiency: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment in patients with renal dysfunction is not necessary (see DOSAGE AND ADMINISTRATION).

Hemodialysis: While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins.

Hepatic Insufficiency: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin 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).

CLINICAL STUDIES

PREVENTION OF CARDIOVASCULAR DISEASE

In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of LIPITOR (atorvastatin calcium) on fatal and non-fatal coronary heart disease was assessed in 10,305 hypertensive patients 40-80 years of age (mean of 63 years), without a previous myocardial infarction and with TC levels 55 years (84.5%), smoking (33.2%), diabetes (24.3%), history of CHD in a first-degree relative (26%), TC:HDL >6 (14.3%), peripheral vascular disease (5.1%), left ventricular hypertrophy (14.4%), prior cer-ebrovascular event (9.8%), specific ECG abnormality (14.3%), proteinuria/albuminuria (62.4%)]. In this double-blind, placebo-controlled study patients were treated with anti-hypertensive therapy (Goal BP <140/90 mm Hg for non-diabetic patients, <130/80 mm Hg for diabetic patients) and allocated to either LIPITOR 10 mg daily (n=5168) or placebo (n=5137), using a covariate adaptive method which took into account the distribution of fourteen baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients were followed for a median duration of 3.3 years.

The effect of 10 mg/day of LIPITOR on lipid levels was similar to that seen in previous clinical trials.

LIPITOR significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the placebo group vs 40 events in the LIPITOR group) or nonfatal MI (108 events in the placebo group vs 60 events in the LIPITOR group)] with a relative risk reduction of 36% [(based on incidences of 1.9% for LIPITOR vs 3.0% for placebo), p=0.0005 (see Figure 1)]. The risk reduction was consistent regardless of age, smoking status, obesity or presence of renal dysfunction. The effect of LIPITOR was seen regardless of baseline LDL levels. Due to the small number of events, results for women were inconclusive.

LIPITOR also significantly decreased the relative risk for revascularization procedures by 42%. Although the reduction of fatal and non-fatal strokes did not reach a pre-defined significance level (p = 0.01), a favorable trend was observed with a 26% relative risk reduction (incidences of 1.7% for LIPITOR and 2.3% for placebo). There was no significant difference between the treatment groups for death due to cardiovascular causes (p=0.51) or noncardiovascular causes (p=0.17).

HYPERCHOLESTEROLEMIA (HETEROZYGOUS FAMILIAL AND NONFAMILIAL) AND MIXED DYSLIPIDEMIA (FREDRICKSON TYPES IIA AND IIB)

Lipitor reduces total-C, LDL-C, VLDL-C, apo B, and TG, and increases HDL-C in patients with hypercholesterolemia and mixed dyslipidemia. Therapeutic response is seen within 2 weeks, and maximum response is usually achieved within 4 weeks and maintained during chronic therapy.

Lipitor is effective in a wide variety of patient populations with hypercholesterolemia, with and without hypertriglyceridemia, in men and women, and in the elderly. Experience in pediatric patients has been limited to patients with homozygous FH. In two multicenter, placebo-controlled, dose-response studies in patients with hypercholesterolemia, Lipitor given as a single dose over 6 weeks significantly reduced total-C, LDL-C, apo B, and TG (Pooled results are provided in Table 1).

In patients with Fredrickson Types IIa and IIb hyperlipoproteinemia pooled from 24 controlled trials, the median (25^th and 75^th percentile) percent changes from baseline in HDL-C for atorvastatin 10, 20, 40, and 80 mg were 6.4 (-1.4, 14), 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.

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).

The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown in Table 2 is not known. Table 2 does not contain data comparing the effects of atorvastatin 10 mg and higher doses of lovastatin, pravastatin, and simvastatin. The drugs compared in the studies summarized in the table are not necessarily interchangeable.

HYPERTRIGLYCERIDEMIA (FREDRICKSON TYPE IV)

The response to Lipitor in 64 patients with isolated hypertriglyceridemia treated across several clinical trials is shown in the table below. For the atorvastatin-treated patients, median (min, max) baseline TG level was 565 (267-1502).

DYSBETALIPOPROTEINEMIA (FREDRICKSON TYPE III)

The results of an open-label crossover study of 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with dysbeta-lipoproteinemia (Fredrickson Type III) are shown in the table below.

HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA

In a study without a concurrent control group, 29 patients ages 6 to 37 years with homozygous FH received maximum daily doses of 20 to 80 mg of Lipitor. The mean LDL-C reduction in this study was 18%. Twenty-five patients with a reduction in LDL-C had a mean response of 20% (range of 7% to 53%, median of 24%); the remaining 4 patients had 7% to 24% increases in LDL-C. Five of the 29 patients had absent LDL-receptor function. Of these, 2 patients also had a portacaval shunt and had no significant reduction in LDL-C. The remaining 3 receptor-negative patients had a mean LDL-C reduction of 22%.

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 of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (FH) or severe hypercholesterolemia were randomized to Lipitor (n=140) or placebo (n=47) for 26 weeks and then all received Lipitor for 26 weeks. Inclusion in the study required 1) a baseline LDL-C level >/= 190 mg/dL or 2) a baseline LDL-C >/= 160 mg/dL and positive family history of FH or documented premature cardiovascular disease in a first- or second-degree relative. The mean baseline LDL-C value was 218.6 mg/dL (range: 138.5-385.0 mg/dL) in the Lipitor group compared to 230.0 mg/dL (range: 160.0-324.5 mg/dL) in the placebo group. The dosage of Lipitor (once daily) was 10 mg for the first 4 weeks and up-titrated to 20 mg if the LDL-C level was > 130 mg/dL. The number of Lipitor-treated patients who required up-titration to 20 mg after Week 4 during the double-blind phase was 80 (57.1%).

Lipitor significantly decreased plasma levels of total-C, LDL-C, triglycerides, and apolipoprotein B during the 26 week double-blind phase (see Table 5).

The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0-242.0 mg/dL) in the Lipitor group compared to 228.5 mg/dL (range: 152.0-385.0 mg/dL) in the placebo group during the 26 week double-blind phase.

The safety and efficacy of doses above 20 mg have not been studied in controlled trials in children. The long-term efficacy of Lipitor therapy in childhood to reduce morbidity and mortality in adulthood has not been established.