12 CLINICAL PHARMACOLOGY
12.1 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. 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, 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)].
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 (2)].
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 (4) and Use in Specific Populations (8.2)].
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 (7.1)]. 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 LIPITOR is recovered in urine following oral administration.
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 (8.5)].
Pediatric: Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in atorvastatin population PK model with data including pediatric HeFH patients (ages 10 years to 17 years of age, n=29) in an open-label, 8-week study.
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 (2.5) and Warnings and Precautions (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 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 (4)].
Drug Interaction Studies
Atorvastatin is a substrate of the hepatic transporters, OATP1B1 and OATP1B3 transporter. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin is also identified as a substrate of the efflux transporter BCRP, which may limit the intestinal absorption and biliary clearance of atorvastatin.
|Co-administered drug and dosing regimen||Atorvastatin|
|Dose (mg)||Ratio of AUC*||Ratio of Cmax*|
|†Cyclosporine 5.2 mg/kg/day, stable dose||10 mg QD‡ for 28 days||8.69||10.66|
|†Tipranavir 500 mg BID§/ritonavir 200 mg BID§, 7 days||10 mg, SD¶||9.36||8.58|
|†Glecaprevir 400 mg QD‡/pibrentasvir 120 mg QD‡, 7 days||10 mg QD‡ for 7 days||8.28||22.00|
|†Telaprevir 750 mg q8h#, 10 days||20 mg, SD¶||7.88||10.60|
|†, ÞSaquinavir 400 mg BID§/ ritonavir 400 mg BID§, 15 days||40 mg QD‡ for 4 days||3.93||4.31|
|†Elbasvir 50 mg QD‡/grazoprevir 200 mg QD‡, 13 days||10 mg SD¶||1.94||4.34|
|†Simeprevir 150 mg QD‡, 10 days||40 mg SD¶||2.12||1.70|
|†Clarithromycin 500 mg BID§, 9 days||80 mg QD‡ for 8 days||4.54||5.38|
|†Darunavir 300 mg BID§/ritonavir 100 mg BID§, 9 days||10 mg QD‡ for 4 days||3.45||2.25|
|†Itraconazole 200 mg QD‡, 4 days||40 mg SD¶||3.32||1.20|
|†Letermovir 480 mg QD‡, 10 days||20 mg SD¶||3.29||2.17|
|†Fosamprenavir 700 mg BID§/ritonavir 100 mg BID§, 14 days||10 mg QD‡ for 4 days||2.53||2.84|
|†Fosamprenavir 1400 mg BID§, 14 days||10 mg QD‡ for 4 days||2.30||4.04|
|†Nelfinavir 1250 mg BID§, 14 days||10 mg QD‡ for 28 days||1.74||2.22|
|†Grapefruit Juice, 240 mL QD‡,ß||40 mg, SD¶||1.37||1.16|
|Diltiazem 240 mg QD‡, 28 days||40 mg, SD¶||1.51||1.00|
|Erythromycin 500 mg QIDà, 7 days||10 mg, SD¶||1.33||1.38|
|Amlodipine 10 mg, single dose||80 mg, SD¶||1.18||0.91|
|Cimetidine 300 mg QIDà, 2 weeks||10 mg QD‡ for 2 weeks||1.00||0.89|
|Colestipol 10 g BID§, 24 weeks||40 mg QD‡ for 8 weeks||NA||0.74è|
|Maalox TC® 30 mL QIDà, 17 days||10 mg QD‡ for 15 days||0.66||0.67|
|Efavirenz 600 mg QD‡, 14 days||10 mg for 3 days||0.59||1.01|
|†Rifampin 600 mg QD‡, 7 days (co-administered) ð||40 mg SD¶||1.12||2.90|
|†Rifampin 600 mg QD‡, 5 days (doses separated) ð||40 mg SD¶||0.20||0.60|
|†Gemfibrozil 600 mg BID§, 7 days||40 mg SD¶||1.35||1.00|
|†Fenofibrate 160 mg QD‡, 7 days||40 mg SD¶||1.03||1.02|
|Boceprevir 800 mg TIDø, 7 days||40 mg SD¶||2.32||2.66|
|Atorvastatin||Co-administered drug and dosing regimen|
|Drug/Dose (mg)||Ratio of AUC||Ratio of Cmax|
|80 mg QD* for 15 days||Antipyrine, 600 mg SD†||1.03||0.89|
|80 mg QD* for 10 days||‡ Digoxin 0.25 mg QD*, 20 days||1.15||1.20|
|40 mg QD* for 22 days||Oral contraceptive QD*, 2 months|
- norethindrone 1 mg
- ethinyl estradiol 35µg
|10 mg, SD†||Tipranavir 500 mg BID§/ritonavir 200 mg BID§, 7 days||1.08||0.96|
|10 mg QD* for 4 days||Fosamprenavir 1400 mg BID§, 14 days||0.73||0.82|
|10 mg QD* for 4 days||Fosamprenavir 700 mg BID§/ritonavir 100 mg BID§, 14 days||0.99||0.94|