Prescription Drug Information: Simvastatin (Page 4 of 7)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

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.

Absorption

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.

Distribution

Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins.

Elimination

Metabolism

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.

Excretion

Following an oral dose of ¹⁴ C-labeled simvastatin, 13% of the dose was excreted in urine and 60% in feces.

Specific Populations

Geriatric Patients

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 Co-administered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure

Co-administered Drug or Grapefruit Juice	Dosing of Co-administered Drug or Grapefruit Juice	Dosing of Simvastatin	Geometric Mean Ratio (Ratio * with / without co-administered drug) No Effect = 1.00
				AUC	C max
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	2.85 1.35	2.18 0.91
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 to 7 then 240 mg BID on Days 8 to 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 to 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 to 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	0.79 0.79	↓ 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 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.

S imvastatin’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.

Co-administration 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) ].