Atorvastatin calcium, 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: Atorvastatin calcium is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin calcium 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 calcium is given with or without food. Plasma atorvastatin calcium 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 atorvastatin calcium is approximately 381 liters. Atorvastatin calcium 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 calcium is likely to be secreted in human milk [see Contraindications, Nursing Mothers (4) and Use in Specific Populations (8.2)].
Metabolism: Atorvastatin calcium 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 calcium. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin calcium metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin calcium 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: Atorvastatin calcium 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 calcium 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 calcium is recovered in urine following oral administration.
Geriatric: Plasma concentrations of atorvastatin calcium 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 atorvastatin calcium 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 atorvastatin calcium between men and women.
Renal Impairment: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin calcium; 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 atorvastatin calcium since the drug is extensively bound to plasma proteins.
Hepatic Impairment: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin calcium 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.
TABLE 4. Effect of Co-administered Drugs on the Pharmacokinetics 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 QDa for 28 days||8.69||10.66|
|# Tipranavir 500 mg BIDb /ritonavir 200 mg BIDb , 7 days||10 mg, SDc||9.36||8.58|
|#Glecaprevir 400 mg QDa /pibrentasvir 120 mg QDa , 7 days||10 mg QDa for 7 days||8.28||22.00|
|# Telaprevir 750 mg q8hf , 10 days||20 mg, SDc||7.88||10.60|
|#, ‡ Saquinavir 400 mg BIDb / ritonavir 400mg BIDb , 15 days||40 mg QD a for 4 days||3.93||4.31|
|#Elbasvir 50 mg QDa /grazoprevir 200 mg QDa , 13 days||10 mg SDc||1.94||4.34|
|#Simeprevir 150 mg QDa , 10 days||40 mg SDc||2.12||1.70|
|# Clarithromycin 500 mg BIDb , 9 days||80 mg QDa for 8 days||4.54||5.38|
|# Darunavir 300 mg BIDb /ritonavir 100 mg BIDb , 9 days||10 mg QDa for 4 days||3.45||2.25|
|# Itraconazole 200 mg QDa , 4 days||40 mg SDc||3.32||1.20|
|# Letermovir 480 mg QDa , 10 days||20 mg SDc||3.29||2.17|
|# Fosamprenavir 700 mg BIDb /ritonavir 100 mg BIDb , 14 days||10 mg QDa for 4 days||2.53||2.84|
|# Fosamprenavir 1400 mg BIDb , 14 days||10 mg QDa for 4 days||2.30||4.04|
|# Nelfinavir 1250 mg BIDb , 14 days||10 mg QDa for 28 days||1.74||2.22|
|# Grapefruit Juice, 240 mL QDa *||40 mg, SDc||1.37||1.16|
|Diltiazem 240 mg QDa , 28 days||40 mg, SDc||1.51||1.00|
|Erythromycin 500 mg QIDe , 7 days||10 mg, SDc||1.33||1.38|
|Amlodipine 10 mg, single dose||80 mg, SDc||1.18||0.91|
|Cimetidine 300 mg QIDe , 2 weeks||10 mg QDa for 2 weeks||1.00||0.89|
|Colestipol 10 g BIDb , 24 weeks||40 mg QDa for 8 weeks||NA||0.74**|
|Maalox TC® 30 mL QIDe , 17 days||10 mg QDa for 15 days||0.66||0.67|
|Efavirenz 600 mg QDa , 14 days||10 mg for 3 days||0.59||1.01|
|# Rifampin 600 mg QDa , 7 days (co-administered) †||40 mg SDc||1.12||2.90|
|# Rifampin 600 mg QDa , 5 days (doses separated) †||40 mg SDc||0.20||0.60|
|# Gemfibrozil 600 mg BIDb , 7 days||40 mg SDc||1.35||1.00|
|# Fenofibrate 160 mg QDa , 7 days||40 mg SDc||1.03||1.02|
|Boceprevir 800 mg TIDd , 7 days||40 mg SDc||2.32||2.66|
& Represents ratio of treatments (co-administered drug plus atorvastatin vs. atorvastatin alone).
# See Sections 5.1 and 7 for clinical significance.
* Greater increases in AUC (ratio of AUC up to 2.5) and/or Cmax (ratio of Cmax up to1.71) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day).
** Ratio based on a 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.
a Once daily
b Twice daily
c Single dose
d Three times daily
e Four times daily
f Every 8 hours
TABLE 5. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs
|Atorvastatin||Co-administered drug and dosing regimen|
|Drug/Dose (mg)||Ratio of AUC||Ratio of Cmax|
|80 mg QDa for 15 days||Antipyrine, 600 mg SDc||1.03||0.89|
|80 mg QDa for 10 days||# Digoxin 0.25 mg QDa , 20 days||1.15||1.20|
|40 mg QDa for 22 days||Oral contraceptive QDa , 2 months — norethindrone 1 mg — ethinyl estradiol 35μg||1.28 1.19||1.23 1.30|
|10 mg, SDc||Tipranavir 500 mg BIDb /ritonavir 200 mg BIDb , 7 days||1.08||0.96|
|10 mg QDa for 4 days||Fosamprenavir 1400 mg BIDb , 14 days||0.73||0.82|
|10 mg QDa for 4 days||Fosamprenavir 700 mgBIDb /ritonavir 100 mg BIDb , 14 days||0.99||0.94|
# See Section 7 for clinical significance.
a Once daily
b Twice daily
c Single dose
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