ATORVASTATIN CALCIUM (Page 6 of 11)

12 CLINICAL PHARMACOLOGY

12.1 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, atorvastatin calcium 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; atorvastatin calcium also reduces LDL production and the number of LDL particles. Atorvastatin calcium 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.

Atorvastatin calcium reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous FH, nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. Atorvastatin calcium also reduces VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-1. Atorvastatin calcium reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia. Atorvastatin calcium 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.

12.2 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 (2)

12.3 Pharmacokinetics

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 C and AUC, LDL-C reduction is similar whether atorvastatin is given with or without food. Plasma atorvastatin concentrations are lower (approximately 30% for C 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 ]. max max Dosage and Administration (2)

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 and ]. Contraindications, Nursing Mothers (4.4)Use in Specific Populations, Nursing Mothers (8.3)

Metabolism

Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. 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 co-administration with erythromycin, a known inhibitor of this isozyme [see ]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation. In vitro Drug Interactions (7.1)

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.

Specific Populations

Geriatric

Plasma concentrations of atorvastatin are higher (approximately 40% for C 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 ]. max Use in Specific Populations, Geriatric Use (8.5)

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 C and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women. max

Renal Impairment

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, Dosage in Patients with Renal Impairment (2.5)Warnings and Precautions, Skeletal Muscle (5.1)

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 Impairment

In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased. C and AUC are each 4-fold greater in patients with Childs-Pugh A disease. C and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see ]. max max Contraindications (4.1)

TABLE 3. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin
Co-administered drug and dosing regimen Atorvastatin
Dose (mg) Change in AUC & Change in Cmax &
Cyclosporine 5.2 mg/kg/day, stable dose # 10 mg QD for 28 days ↑ 8.7 fold ↑10.7 fold
Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days # 10 mg, SD ↑ 9.4 fold ↑ 8.6 fold
Telaprevir 750 mg q8h, 10 days # 20 mg, SD ↑ 7.88 fold ↑ 10.6 fold
Saquinavir 400 mg BID/ ritonavir 400mg BID, 15 days #, ‡ 40 mg QD for 4 days ↑ 3.9 fold ↑ 4.3 fold
Clarithromycin 500 mg BID, 9 days # 80 mg QD for 8 days ↑ 4.4 fold ↑ 5.4 fold
Darunavir 300 mg BID/ritonavir 100 mg BID, 9 days # 10 mg QD for 4 days ↑ 3.4 fold ↑ 2.25 fold
Itraconazole 200 mg QD, 4 days # 40 mg SD ↑ 3.3 fold ↑ 20%
Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days # 10 mg QD for 4 days ↑ 2.53 fold ↑ 2.84 fold
Fosamprenavir 1400 mg BID, 14 days # 10 mg QD for 4 days ↑ 2.3 fold ↑ 4.04 fold
Nelfinavir 1250 mg BID, 14 days # 10 mg QD for 28 days ↑ 74% ↑ 2.2 fold
Grapefruit Juice, 240 mL QD # * 40 mg, SD ↑ 37% ↑ 16%
Diltiazem 240 mg QD, 28 days 40 mg, SD ↑ 51% No change
Erythromycin 500 mg QID, 7 days 10 mg, SD ↑ 33% ↑ 38%
Amlodipine 10 mg, single dose 80 mg, SD ↑ 15% ↓ 12 %
Cimetidine 300 mg QD, 4 weeks 10 mg QD for 2 weeks ↓ Less than 1% ↓ 11%
Colestipol 10 mg BID, 28 weeks 40 mg QD for 28 weeks Not determined ↓ 26% **
Maalox TC® 30 mL QD, 17 days 10 mg QD for 15 days ↓ 33% ↓ 34%
Efavirenz 600 mg QD, 14 days 10 mg for 3 days ↓ 41% ↓ 1%
Rifampin 600 mg QD, 7 days (coadministered) # 40 mg SD ↑ 30% ↑ 2.7 fold
Rifampin 600 mg QD, 5 days (doses separated) # 40 mg SD ↓ 80% ↓ 40%
Gemfibrozil 600mg BID, 7 days # 40mg SD ↑ 35% ↓ Less than 1%
Fenofibrate 160mg QD, 7 days # 40mg SD ↑ 3% ↑ 2%

Data given as x-fold change represent a simple ratio between co-administration and atorvastatin alone (i.e., 1-fold = no change). Data given as % change represent % difference relative to atorvastatin alone (i.e., 0% = no change). &

See Sections 5.1 and 7 for clinical significance. #

* Greater increases in AUC (up to 2.5 fold) and/or C (up to 71%) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day). max

** Single sample taken 8 to 16 h post dose.

Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.

The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used.

TABLE 4. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs
Atorvastatin Co-administered drug and dosing regimen
Drug/Dose (mg) Change in AUC Change in Cmax
80 mg QD for 15 days Antipyrine, 600 mg SD ↑ 3% ↓ 11%
80 mg QD for 14 days Digoxin 0.25 mg QD, 20 days # ↑ 15% ↑ 20 %
40 mg QD for 22 days Oral contraceptive QD, 2 months — norethindrone 1mg — ethinyl estradiol 35mcg ↑ 28% ↑ 19% ↑ 23% ↑ 30%
10 mg, SD Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days No change No change
10 mg QD for 4 days Fosamprenavir 1400 mg BID, 14 days ↓ 27% ↓ 18%
10 mg QD for 4 days Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days No change No change

See Section 7 for clinical significance. #

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