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LIPITOR® (atorvastatin calcium) Clinical Pharmacology

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.

12.2 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 (2)].

12.3 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 (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.

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 (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.

TABLE 4. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin
Co-administered drug and dosing regimenAtorvastatin
Dose (mg)Ratio of AUC*Ratio of Cmax*
*
Represents ratio of treatments (co-administered drug plus atorvastatin vs. atorvastatin alone).
See Sections 5.1 and 7 for clinical significance.
Once daily
§
Twice daily
Single dose
#
Every 8 hours
Þ
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.
ß
Greater increases in AUC (ratio of AUC up to 2.5) and/or Cmax (ratio of Cmax up to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL – 1.2 liters per day).
à
Four times daily
è
Ratio based on a single sample taken 8–16 h post dose.
ð
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.
ø
Three times daily
Cyclosporine 5.2 mg/kg/day, stable dose10 mg QD for 28 days8.6910.66
Tipranavir 500 mg BID§/ritonavir 200 mg BID§, 7 days10 mg, SD9.368.58
Glecaprevir 400 mg QD/pibrentasvir 120 mg QD, 7 days10 mg QD for 7 days8.2822.00
Telaprevir 750 mg q8h#, 10 days20 mg, SD7.8810.60
, ÞSaquinavir 400 mg BID§/ ritonavir 400 mg BID§, 15 days40 mg QD for 4 days3.934.31
Elbasvir 50 mg QD/grazoprevir 200 mg QD, 13 days10 mg SD1.944.34
Simeprevir 150 mg QD, 10 days40 mg SD2.121.70
Clarithromycin 500 mg BID§, 9 days80 mg QD for 8 days4.545.38
Darunavir 300 mg BID§/ritonavir 100 mg BID§, 9 days10 mg QD for 4 days3.452.25
Itraconazole 200 mg QD, 4 days40 mg SD3.321.20
Letermovir 480 mg QD, 10 days20 mg SD3.292.17
Fosamprenavir 700 mg BID§/ritonavir 100 mg BID§, 14 days10 mg QD for 4 days2.532.84
Fosamprenavir 1400 mg BID§, 14 days10 mg QD for 4 days2.304.04
Nelfinavir 1250 mg BID§, 14 days10 mg QD for 28 days1.742.22
Grapefruit Juice, 240 mL QD,ß40 mg, SD1.371.16
Diltiazem 240 mg QD, 28 days40 mg, SD1.511.00
Erythromycin 500 mg QIDà, 7 days10 mg, SD1.331.38
Amlodipine 10 mg, single dose80 mg, SD1.180.91
Cimetidine 300 mg QIDà, 2 weeks10 mg QD for 2 weeks1.000.89
Colestipol 10 g BID§, 24 weeks40 mg QD for 8 weeksNA0.74è
Maalox TC® 30 mL QIDà, 17 days10 mg QD for 15 days0.660.67
Efavirenz 600 mg QD, 14 days10 mg for 3 days0.591.01
Rifampin 600 mg QD, 7 days (co-administered) ð40 mg SD1.122.90
Rifampin 600 mg QD, 5 days (doses separated) ð40 mg SD0.200.60
Gemfibrozil 600 mg BID§, 7 days40 mg SD1.351.00
Fenofibrate 160 mg QD, 7 days40 mg SD1.031.02
Boceprevir 800 mg TIDø, 7 days40 mg SD2.322.66
TABLE 5. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Drugs
AtorvastatinCo-administered drug and dosing regimen
Drug/Dose (mg)Ratio of AUCRatio of Cmax
*
Once daily
Single dose
See Section 7 for clinical significance.
§
Twice daily
80 mg QD* for 15 daysAntipyrine, 600 mg SD1.030.89
80 mg QD* for 10 days Digoxin 0.25 mg QD*, 20 days1.151.20
40 mg QD* for 22 daysOral contraceptive QD*, 2 months
- norethindrone 1 mg
- ethinyl estradiol 35µg
1.28
1.19
1.23
1.30
10 mg, SDTipranavir 500 mg BID§/ritonavir 200 mg BID§, 7 days1.080.96
10 mg QD* for 4 daysFosamprenavir 1400 mg BID§, 14 days0.730.82
10 mg QD* for 4 daysFosamprenavir 700 mg BID§/ritonavir 100 mg BID§, 14 days0.990.94

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