Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

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 (3)].

Pharmacokinetic Properties

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 .

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.

Elimination
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 (8.1)]. 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.

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.

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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 [see Use in Specific Populations (9.6)].

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 Use in Specific Populations (9.7)].

Drug Interaction

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 6. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin Co-administered drug and                                      Atorvastatin dosing regimen
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
10 mg, SDc                 9.36               8.58
200 mg BIDb, 7 days
#
Glecaprevir 400 mg QDa/pibrentasvir
10 mg QDa for 7 days       8.28               22.00
120 mg QDa, 7 days
#
Telaprevir 750 mg q8hf, 10 days            20 mg, SDc                 7.88               10.60 #, ‡
Saquinavir 400 mg BIDb/ ritonavir                  a
40 mg QD for 4 days        3.93               4.31
400 mg BIDb, 15 days
#
Elbasvir 50 mg QDa/grazoprevir 200 mg
10 mg SDc                  1.94               4.34
QDa, 13 days
#
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
10 mg QDa for 4 days       3.45               2.25
100 mg BIDb, 9 days
#
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
10 mg QDa for 4 days       2.53               2.84
100 mg BIDb, 14 days
#
Fosamprenavir 1400 mg BIDb, 14 days                  a
10 mg QD 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 

Lipitor LPD WC 160424


Co-administered drug and                                      Atorvastatin dosing regimen
Dose (mg)                   Ratio of AUC&      Ratio of
Cmax&
Efavirenz 600 mg QDa, 14 days                 10 mg for 3 days             0.59            1.01 #
Rifampin 600 mg QDa, 7 days                            c
40 mg SD                     1.12                2.90
(co-administered) †
#
Rifampin 600 mg QDa, 5 days (doses
40 mg SDc                    0.20                0.60 separated)†
#
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 to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL - 1.2 liters per day).
** Ratio based on a 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.
‡
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 7. 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
Oral contraceptive QDa, 2 months
40 mg QDa for 22 days      - norethindrone 1 mg                  1.28                    1.23
- ethinyl estradiol 35µg              1.19                    1.30 c                Tipranavir 500 mg BIDb/ritonavir
10 mg, SD                                                        1.08                    0.96 200 mg BIDb, 7 days
Fosamprenavir 1400 mg BIDb,
10 mg QDa for 4 days                                             0.73                    0.82 14 days
Fosamprenavir 700 mg
10 mg QDa for 4 days                                             0.99                    0.94 BIDb/ritonavir 100 mg BIDb, 14 days
#
See Section 7 for clinical significance.
a
Once daily b
Twice daily c
Single dose
LIPITOR had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.