Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
Epidemiological studies have demonstrated that elevated levels of total-C, LDL-C, as well as decreased levels of HDL-C are associated with the development of atherosclerosis and increased cardiovascular risk. Lowering LDL-C decreases this risk. However, the independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

Pharmacokinetic Properties

12.3 Pharmacokinetics
Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of simvastatin.



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Following an oral dose of C-labeled simvastatin in man, 13% of the dose was excreted in urine and 14
60% in feces. Plasma concentrations of total radioactivity (simvastatin plus C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. Since simvastatin undergoes extensive first-pass extraction in the liver, the availability of the drug to the general circulation is low (<5%).
Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. Rat studies indicate that when radiolabeled simvastatin was administered, simvastatin- derived radioactivity crossed the blood-brain barrier.
The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of simvastatin and its 6′-hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives. Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. While the recommended therapeutic dose range is 5 to 40 mg/day, there was no substantial deviation from linearity of AUC of inhibitors in the general circulation with an increase in dose to as high as 120 mg. Relative to the fasting state, the plasma profile of inhibitors was not affected when simvastatin was administered immediately before an American Heart Association recommended low-fat meal.
In a study including 16 elderly patients between 70 and 78 years of age who received SIMOVIL 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately
45% compared with 18 patients between 18-30 years of age. Clinical study experience in the elderly
(n=1522), suggests that there were no overall differences in safety between elderly and younger patients [see Use in Specific Populations (8.5)].
Kinetic studies with another statin, having a similar principal route of elimination, have suggested that for a given dose level higher systemic exposure may be achieved in patients with severe renal insufficiency (as measured by creatinine clearance).
Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of statins. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1. (See CONTRAINDICATIONS)
The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma.
Inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].



TABLE 3
Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure 
Geometric Mean Ratio
(Ratio* with / without
Coadministered Drug            Dosing of Coadministered            Dosing of coadministered drug) or Grapefruit Juice            Drug or Grapefruit Juice          Simvastatin No Effect = 1.00
AUC           C max
Contraindicated with simvastatin [see Contraindications (4) and Warnings and Precautions (5.1)] †                                                                                  ‡ Telithromycin                    200 mg QD for 4 days               80 mg           simvastatin acid          12            15 simvastatin               8.9           5.3
†                                                                                       ‡ Nelfinavir                     1250 mg BID for 14 days         20 mg QD for 28      simvastatin acid days            simvastatin                6           6.2
†                                                                                   ‡ Itraconazole                     200 mg QD for 4 days              80 mg            simvastatin acid                       13.1 simvastatin                            13.1
Posaconazole                   100 mg (oral suspension)             40 mg           simvastatin acid          7.3          9.2 QD for 13 days                                   simvastatin               10.3         9.4 
200 mg (oral suspension)             40 mg           simvastatin acid           8.5         9.5 QD for 13 days                                   simvastatin               10.6         11.4 Gemfibrozil                     600 mg BID for 3 days               40 mg           simvastatin acid          2.85         2.18 simvastatin               1.35         0.91
Avoid grapefruit juice with simvastatin [see Warnings and Precautions (5.1)] Grapefruit Juice§             200 mL of double-strength       60 mg single dose     simvastatin acid           7 (high dose)                               TID¶                                      simvastatin               16 §
Grapefruit Juice             8 oz (about 237mL) of single-    20 mg single dose     simvastatin acid          1.3 (low dose)                             strength#                                    simvastatin               1.9 Avoid taking with >10 mg simvastatin, based on clinical and/or post-marketing experience [see Warnings and Precautions (5.1)] Verapamil SR                   240 mg QD Days 1-7 then        80 mg on Day 10       simvastatin acid          2.3           2.4 240 mg BID on Days 8-10                              simvastatin               2.5           2.1 Diltiazem                       120 mg BID for 10 days        80 mg on Day 10       simvastatin acid          2.69         2.69 simvastatin               3.10         2.88
Diltiazem                       120 mg BID for 14 days        20 mg on Day 14       simvastatin               4.6           3.6 Dronedarone                     400 mg BID for 14 days        40 mg QD for 14            simvastatin             1.96          2.1 days                  acid                 3.90              4 simvastatin                            3.75
Avoid taking with >20 mg simvastatin, based on clinical and/or post-marketing experience [see Warnings and Precautions (5.1)] Amiodarone                       400 mg QD for 3 days          40 mg on Day 3  simvastatin acid    1.75          1.72 simvastatin         1.76          1.79
Amlodipine                  10 mg QD x 10 days          80 mg on Day 10        simvastatin acid    1.58          1.56 simvastatin         1.77          1.47
Ranolazine SR             1000 mg BID for 7 days       80 mg on Day 1 and      simvastatin acid    2.26          2.28 Days 6-9           simvastatin         1.86          1.75
Avoid taking with >20 mg simvastatin (or 40 mg for patients who have previously taken 80 mg simvastatin chronically, e.g., for 12 months or more, without evidence of muscle toxicity), based on clinical experience Lomitapide                 60 mg QD for 7 days          40 mg single dose      simvastatin acid     1.7           1.6 simvastatin           2             2
Lomitapide                 10 mg QD for 7 days          20 mg single dose      simvastatin acid     1.4           1.4 simvastatin          1.6           1.7
No dosing adjustments required for the following:
Fenofibrate                     160 mg QD X 14 days           80 mg QD on Days      simvastatin acid          0.64         0.89 8-14            simvastatin               0.89         0.83
Niacin                              2 g single dose           20 mg single dose     simvastatin acid          1.6          1.84 extended-release Þ                                                                  simvastatin               1.4          1.08 Propranolol                       80 mg single dose           80 mg single dose     total inhibitor           0.79        ↓ from 33.6 to
21.1 ng·eq/mL

↓ from active inhibitor          0.79       7.0 to 4.7 ng·eq/mL
*
Results based on a chemical assay except results with propranolol as indicated.
†
Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone.
‡
Simvastatin acid refers to the β-hydroxyacid of simvastatin.
§
The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied.
¶
Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3.
#
Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3.



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Because Chinese patients have an increased risk for myopathy with simvastatin coadministered with lipid-modifying doses (≥ 1 gram/day niacin) of niacin-containing products, and the risk is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid- modifying doses of niacin-containing products [see Warnings and Precautions (5.1) and Drug Interactions (7.8)].

In a study of 12 healthy volunteers, simvastatin at the 80-mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4, and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4.
Coadministration of simvastatin (40 mg QD for 10 days) resulted in an increase in the maximum mean levels of cardioactive digoxin (given as a single 0.4 mg dose on day 10) by approximately 0.3 ng/mL.