Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin acid and its metabolites are inhibitors of HMG-CoA reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonate, a precursor of cholesterol.
Inhibition of HMG-CoA reductase by simvastatin acid accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of simvastatin is usually achieved by 4 weeks and is maintained after that.
Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid. Pharmacokinetics (PK) of simvastatin and its metabolites was originally characterized using inhibition of HMG-CoA reductase activity following base hydrolysis of plasma samples, as specific bioanalytical methods were not available. Inhibition of the enzyme activity (equivalent to the level of total inhibitors) represented the combination of activities in plasma following administration of simvastatin from both active (simvastatin acid and its metabolites) and latent forms (simvastatin and its metabolites) after conversion to the active forms in the presence of base.
Following an oral dose of 14 C-labeled simvastatin, plasma concentrations of total radioactivity (simvastatin plus 14 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 simvastatin to the general circulation is low (<5%). PK, assessed as area under the concentrations of total inhibitors – time curve, was apparently linear with doses up to 120 mg.
Effect of Food
The plasma profile of total inhibitors concentration was not affected when simvastatin was administered with low fat meal.
Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins.
Simvastatin is metabolized by CYP3A4. The major active metabolites of simvastatin present in human plasma are simvastatin acid 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.
Following an oral dose of 14 C-labeled simvastatin, 13% of the dose was excreted in urine and 60% in feces.
In a study including 16 geriatric patients between 70 and 78 years of age who received simvastatin 40 mg/day, the mean plasma level of total inhibitors was increased approximately 45% compared with 18 patients between 18 to 30 years of age [see Use in Specific Populations ( 8.5)].
Drug Interaction Studies
Simvastatin acid is a substrate of the transport protein OATP1B1. Concomitant administration of inhibitors of the transport protein OATP1B1 and/or CYP3A4 may lead to increased exposure of simvastatin acid. Cyclosporine has been shown to increase the AUC of statins; although the mechanism is not fully understood, the increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4 and/or OATP1B1 [see Drug Interactions ( 7)].
Table 4 displays the effect of coadministered drugs or grapefruit juice on simvastatin systemic exposure [see Drug Interactions ( 7)]. Table 4: Effect of Coadministered Drugs or Grapefruit Juice on simvastatin Systemic Exposure
|Coadministered Drug or Grapefruit Juice||Dosing of Coadministered Drug or Grapefruit Juice||Dosing of Simvastatin||Geometric Mean Ratio (Ratio * with / without coadministered drug) No Effect = 1.00|
|Telithromycin †||200 mg QD for 4 days||80 mg||simvastatin acid ‡ simvastatin||12 8.9||15 5.3|
|Nelfinavir †||1250 mg BID for 14 days||20 mg QD for 28 days||simvastatin acid ‡ simvastatin||6||6.2|
|Itraconazole †||200 mg QD for 4 days||80 mg||simvastatin acid ‡ simvastatin||13.1 13.1|
|Posaconazole||100 mg (oral suspension) QD for 13 days 200 mg (oral suspension) QD for 13 days||40 mg 40 mg||simvastatin acid simvastatin simvastatin acid simvastatin||7.3 10.3 8.5 10.6||9.2 9.4 9.5 11.4|
|Gemfibrozil||600 mg BID for 3 days||40 mg||simvastatin acid simvastatin|| |
|Grapefruit Juice § (high dose)||200 mL of double-strength TID ¶||60 mg single dose||simvastatin acid simvastatin||7 16|
|Grapefruit Juice § (low dose)||8 oz (about 237 mL) of single-strength #||20 mg single dose||simvastatin acid simvastatin||1.3 1.9|
|Verapamil SR||240 mg QD days 1-7 then 240 mg BID on Days 8-10||80 mg on Day 10||simvastatin acid simvastatin||2.3 2.5||2.4 2.1|
|Diltiazem||120 mg BID for 10 days||80 mg on Day 10||simvastatin acid simvastatin||2.69 3.10||2.69 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 days||simvastatin acid simvastatin||1.96 3.90||2.14 3.75|
|Amiodarone||400 mg QD for 3 days||40 mg on Day 3||simvastatin acid simvastatin||1.75 1.76||1.72 1.79|
|Amlodipine||10 mg QD x 10 days||80 mg on Day 10||simvastatin acid simvastatin||1.58 1.77||1.56 1.47|
|Ranolazine SR||1000 mg BID for 7 days||80 mg on Day 1 and Days 6-9||simvastatin acid simvastatin||2.26 1.86||2.28 1.75|
|Lomitapide||60 mg QD for 7 days||40 mg single dose||simvastatin acid simvastatin||1.7 2||1.6 2|
|Lomitapide||10 mg QD for 7 days||20 mg single dose||simvastatin acid simvastatin||1.4 1.6||1.4 1.7|
|Fenofibrate||160 mg QD X 14 days||80 mg QD on Days 8-14||simvastatin acid simvastatin||0.64 0.89||0.89 0.83|
|Niacin extended-release||2 g single dose||20 mg single dose||simvastatin acid simvastatin||1.6 1.4||1.84 1.08|
|Propranolol||80 mg single dose||80 mg single dose||total inhibitor active inhibitor|| |
|↓ from 33.6 to 21.1 ng·eq/ML ↓ from 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, 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.
Simvastatin’s Effect on the Pharmacokinetics of Other Drugs
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. Simvastatin is not an inhibitor of CYP3A4 and 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 [see Drug Interactions ( 7.2) ].
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