Lipitor (Page 6 of 11)

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

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, Geriatric Use (8.5)].

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

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, 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 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 (4.1)].

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 *
*
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 Cmax (up to 71%) have been reported with excessive grapefruit consumption (≥ 750 mL – 1.2 liters per day).
§
Single sample taken 8–16 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.
Cyclosporine 5.2 mg/kg/day, stable dose 10 mg QD for 28 days ↑ 8.7 fold ↑10.7 fold
Lopinavir 400 mg BID/ ritonavir 100 mg BID, 14 days 20 mg QD for 4 days ↑ 5.9 fold ↑ 4.7 fold
Ritonavir 400 mg BID/ saquinavir 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
Itraconazole 200 mg QD, 4 days 40 mg SD ↑ 3.3 fold ↑ 20%
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 (co-administered) 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%
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
*
See Section 7 for clinical significance.
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 35µg ↑ 28% ↑ 19% ↑ 23% ↑ 30%

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