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Simcor (Simvastatin / Niacin) - Description and Clinical Pharmacology

 
 



DESCRIPTION

SIMCOR tablets contain niacin extended-release (NIASPAN) and simvastatin in combination. Simvastatin, an inhibitor of HMG-CoA reductase, and niacin are both lipid-altering agents.

Niacin Extended-Release

Niacin is nicotinic acid, or 3-pyridinecarboxylic acid. Niacin is a white, nonhygroscopic crystalline powder that is very soluble in water, boiling ethanol, and propylene glycol. It is insoluble in ethyl ether. The empirical formula of niacin is C6H5NO2 and its molecular weight is 123.11. Niacin has the following structural formula:

Simvastatin

Simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3-7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S-[1α,3α,7β,8β(2S*4S*),-8aβ]]. Simvastatin is a white to off-white, nonhygroscopic, crystalline powder that is practically insoluble in water and freely soluble in chloroform, methanol, and ethanol. The empirical formula of simvastatin is C25H38O5 and its molecular weight is 418.57. Simvastatin has the following structural formula:

SIMCOR is available for oral administration as tablets containing 500 mg of extended-release niacin (NIASPAN) and 20 mg simvastatin (SIMCOR 500/20), 750 mg of extended-release niacin (NIASPAN) and 20 mg simvastatin (SIMCOR 750/20), and 1000 mg of extended-release niacin (NIASPAN) and 20 mg simvastatin (SIMCOR 1000/20). Each tablet contains the following inactive ingredients: hypromellose, povidone, stearic acid, polyethylene glycol, butylated hydroxyanisole, a blue Opadry® color coat (FD&C Blue #2, hypromellose, lactose monohydrate, titanium dioxide, triacetin), and a clear Opadry® coat (hypromellose, polyethylene glycol).

CLINICAL PHARMACOLOGY

Mechanism of Action

Niacin

Niacin functions in the body after conversion to nicotinamide adenine dinucleotide (NAD) in the NAD coenzyme system. The mechanism by which niacin alters lipid profiles is not completely understood and may involve several actions, including partial inhibition of release of free fatty acids from adipose tissue, and increased lipoprotein lipase activity (which may increase the rate of chylomicron triglyceride removal from plasma). Niacin decreases the rate of hepatic synthesis of VLDL-C and LDL-C, and does not appear to affect fecal excretion of fats, sterols, or bile acids.

Simvastatin

Simvastatin is a prodrug and is hydrolyzed to its active ß-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C.

Pharmacodynamics

A variety of clinical studies have demonstrated that elevated levels of Total-C, LDL-C, and Apo B promote human atherosclerosis. Similarly, decreased levels of HDL-C are associated with the development of atherosclerosis. Epidemiological investigations have established that cardiovascular morbidity and mortality vary directly with the level of Total-C and LDL-C, and inversely with the level of HDL-C.

Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate-density lipoprotein (IDL), and their remnants, can also promote atherosclerosis. Elevated plasma TG are frequently found in a triad with low HDL-C levels and small LDL particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease (CHD). As such, total plasma TG has not consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

SIMCOR

SIMCOR reduces total-C, LDL-C, non-HDL-C, Apo B, TG, and Lp(a) levels and increases HDL-C in patients with primary type II hyperlipidemia (heterozygous familial and nonfamilial), mixed dyslipidemia, or hypertriglyceridemia.

Niacin

Niacin (but not nicotinamide) in gram doses reduces LDL-C, Apo B, Lp(a), TG, and Total-C, and increases HDL-C. The magnitude of individual lipid and lipoprotein responses may be influenced by the severity and type of underlying lipid abnormality. The increase in HDL-C is associated with an increase in apolipoprotein A-I (Apo A-I) and a shift in the distribution of HDL subfractions. These shifts include an increase in the HDL2:HDL3 ratio, and an elevation in lipoprotein A-I (Lp A-I, an HDL-C particle containing only Apo A-I). Niacin treatment also decreases serum levels of apolipoprotein B-100 (Apo B), the major protein component of the very low-density lipoprotein (VLDL) and LDL fractions, and of Lp(a), a variant form of LDL independently associated with coronary risk. In addition, preliminary reports suggest that niacin causes favorable LDL particle size transformations, although the clinical relevance of this effect requires further investigation.

Simvastatin

Simvastatin reduces elevated total-C, LDL-C, Apo B, and TG, and increases HDL-C in patients with primary heterozygous familial and nonfamilial hypercholesterolemia and mixed dyslipidemia. Simvastatin reduces total-C and LDL-C in patients with homozygous familial hypercholesterolemia. Simvastatin decreases VLDL, total-C/HDL-C ratio, and LDL-C/HDL-C ratio.

Pharmacokinetics

Absorption and Bioavailability

SIMCOR

The relative bioavailability of niacin (Nicotinuric acid, NUA, Cmax and total urinary excretion as the surrogate), simvastatin, and simvastatin acid was evaluated under a light snack conditions in healthy volunteers (n=42), following administration of two 1000/20 mg SIMCOR tablets. Niacin exposure (Cmax and AUC) after SIMCOR was similar to that of a niacin extended-release formulation. However, simvastatin and simvastatin acid AUC after SIMCOR increased by 23% and 41%, respectively, compared to those of a simvastatin immediate release formulation. The mean time to Cmax (Tmax) for niacin ranged from 4.6 to 4.9 hours and simvastatin from 1.9 to 2.0 hours. Following administration of 2 x 1000/20 mg SIMCOR, the mean Cmax, Tmax and AUC(0-t) for simvastatin acid, active metabolite of simvastatin, were 3.29 ng/mL, 6.56 hours and 30.81 ng.hr/mL respectively.

Bioequivalence has not been evaluated among different SIMCOR dosage strengths. Therefore, dosage strengths of SIMCOR should not be considered exchangeable.

Niacin

Due to extensive and saturable first-pass metabolism, niacin concentrations in the general circulation are dose dependent and highly variable. Peak steady-state niacin concentrations were 0.6, 4.9, and 15.5 mcg/mL after doses of 1000, 1500, and 2000 mg NIASPAN once daily (given as two 500 mg, two 750 mg, and two 1000 mg tablets, respectively). To reduce the risk of gastrointestinal upset, administration of niacin extended-release with a low-fat meal or snack is recommended.

Simvastatin

Since simvastatin undergoes extensive first-pass extraction in the liver, the availability of the drug to the general circulation is low (<5%). Peak plasma concentrations of both active and total inhibitors were attained within 1.3 to 2.4 hours postdose. Following an oral dose of 14C-labeled simvastatin in man, plasma concentration of total radioactivity (simvastatin plus 14C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose. 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.

Metabolism

SIMCOR

Following administration of SIMCOR, niacin and simvastatin undergo rapid and extensive first-pass metabolism as described in the following niacin and simvastatin sections. Following administration of 2 x 1000/20 mg SIMCOR in healthy volunteers, 10.2%, 10.7%, and 29.5% of the administered niacin dose was recovered in urine as niacin metabolites, nicotinuric acid (NUA), N-methylnicotinamide (MNA), and N-methyl-2-pyridone-5-carboxamide (2PY), respectively. Following administration of 2 x 1000/20 mg SIMCOR, the mean Cmax, Tmax, and AUC(0-t) for the simvastatin metabolite, simvastatin acid were 3.29 ng/mL, 6.56 hours, and 30.81 ng·hr/mL respectively.

Niacin

Niacin undergoes rapid and extensive first-pass metabolism that is dose-rate specific and, at the doses used to treat dyslipidemia, saturable. In humans, one pathway is through a simple conjugation step with glycine to form NUA. NUA is then excreted, although there may be a small amount of reversible metabolism back to niacin. The other pathway results in the formation of nicotinamide adenine dinucleotide (NAD). It is unclear whether nicotinamide is formed as a precursor to, or following the synthesis of, NAD. Nicotinamide is further metabolized to at least MNA and nicotinamide-N-oxide NNO. MNA is further metabolized to two other compounds, 2PY and N-methyl-4-pyridone-5-carboxamide (4PY). The formation of 2PY appears to predominate over 4PY in humans.

Simvastatin

Simvastatin is a substrate of CYP3A4. Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. 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.

Elimination

SIMCOR

Following 2 x 1000/20 mg SIMCOR administration, approximately 54% of the niacin dose administered was recovered in urine in 96 hours as niacin and metabolites of which 3.6% was recovered as niacin.

After SIMCOR administration, the mean terminal plasma half-life for simvastatin was 4.2 to 4.9 hours and for simvastatin acid was 4.6 to 5.0 hours.

Niacin

Niacin and its metabolites are rapidly eliminated in the urine. Following single and multiple doses of 1500 to 2000 mg niacin, approximately 53 to 77% of the niacin dose administered as NIASPAN was recovered in urine as niacin and metabolites; up to 7.7% of the dose was recovered in urine as unchanged niacin after multiple dosing with 2 x 1000 mg NIASPAN. The ratio of metabolites recovered in the urine was dependent on the dose administered.

Simvastatin

Simvastatin is excreted in urine, based on studies in humans. Following an oral dose of 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces.

Special Populations

A pharmacokinetic study with simvastatin showed the mean plasma level of HMG-CoA reductase inhibitory activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age.

Steady-state plasma concentrations of niacin and metabolites after administration of niacin extended-release are generally higher in women than in men, with the magnitude of the difference varying with dose and metabolite. Recovery of niacin and metabolites in urine, however, is generally similar for men and women, indicating that absorption is similar for both genders. The gender differences observed in plasma levels of niacin and its metabolites may be due to gender-specific differences in metabolic rate or volume of distribution.

Pharmacokinetic studies with a statin having a similar principal route of elimination to that of simvastatin 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).

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted with SIMCOR regarding carcinogenesis, mutagenesis, or impairment of fertility.

Niacin

Niacin, administered to mice for a lifetime as a 1% solution in drinking water, was not carcinogenic. The mice in this study received approximately 6 to 8 times a human dose of 3000 mg/day as determined on a mg/m2 basis. Niacin was negative for mutagenicity in the Ames test. No studies on impairment of fertility have been performed.

Simvastatin

In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of 25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approximately 1, 4, and 8 times higher than the mean human plasma drug level, respectively (as total inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males with a maximum incidence of 90% in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No evidence of a tumorigenic effect was observed at 25 mg/kg/day.

In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than humans given 80 mg simvastatin as measured by AUC). In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC). A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produced hepatocellular adenomas and carcinomas (in female rats at both doses and in males at 100 mg/kg/day). Thyroid follicular cell adenomas were increased in males and females at both doses; thyroid follicular cell carcinomas were increased in females at 100 mg/kg/day. The increased incidence of thyroid neoplasms appears to be consistent with findings from other HMG-CoA reductase inhibitors. These treatment levels represented plasma drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25 times (females) the mean human plasma drug exposure after an 80 milligram daily dose. No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow. There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg body weight (4 times the maximum human exposure level, based on AUC, in patients receiving 80 mg/day); however, this effect was not observed during a subsequent fertility study in which simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes of rats from either study. At 180 mg/kg/day, (which produces exposure levels 22 times higher than those in humans taking 80 mg/day based on surface area, mg/m2), seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation at 10 mg/kg/day, (approximately 2 times the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings is unclear.

Animal Toxicology and/or Pharmacology

SIMCOR

No animal toxicology or pharmacology studies were done with SIMCOR.

Niacin

No animal toxicology or pharmacology studies were done with niacin extended-release.

Simvastatin

Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at 180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times higher than the mean plasma drug level in humans taking 80 mg/day. A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.

Central Nervous System (CNS) vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels were seen in dogs treated with simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug levels that were about 14 times higher than the mean plasma drug levels in humans taking 80 mg/day. Similar CNS vascular lesions have been observed with several other drugs of this class.

There were cataracts in female rats after two years of simvastatin treatment with 50 and 100 mg/kg/day (22 and 25 times the human AUC at 80 mg/day, respectively) and in dogs after three months at 90 mg/kg/day (19 times) and at two years at 50 mg/kg/day (5 times).

Reproductive Toxicology Studies

Simvastatin was not teratogenic in rats at doses of 25 mg/kg/day or in rabbits at doses up to 10 mg/kg/day. These doses resulted in 3 times (rat) or 3 times (rabbit) the human exposure based on mg/m2 surface area. However, in studies with another structurally-related HMG-CoA reductase inhibitor, skeletal malformations were observed in rats and mice.

CLINICAL STUDIES

Modifications of Lipid Profiles

SIMCOR

In a double-blind, randomized, multicenter, multi-national, active-controlled, 24-week study, the lipid effects of SIMCOR were compared to simvastatin 20 mg and 80 mg in 641 patients with type II hyperlipidemia or mixed dyslipidemia. Following a lipid qualification phase, patients were eligible to enter one of two treatment groups. In Group A, patients on simvastatin 20 mg monotherapy, with elevated non-HDL levels and LDL-C levels at goal per the NCEP guidelines, were randomized to one of three treatment arms: SIMCOR 1000/20 mg, SIMCOR 2000/20 mg, or simvastatin 20 mg. In Group B, patients on simvastatin 40 mg monotherapy, with elevated non-HDL levels per the NCEP guidelines regardless of attainment of LDL-C goals, were randomized to one of three treatment arms: SIMCOR 1000/40 mg, SIMCOR 2000/40 mg, or simvastatin 80 mg. Therapy was initiated at the 500 mg dose of SIMCOR and increased by 500 mg every four weeks. Thus patients were titrated to the 1000 mg dose of SIMCOR after four weeks and to the 2000 mg dose of SIMCOR after 12 weeks. All patients randomized to simvastatin monotherapy received 50 mg immediate-release niacin daily in an attempt to keep the study from becoming unblinded due to flushing in the SIMCOR groups. Patients were instructed to take one 325 mg aspirin or 200 mg ibuprofen 30 minutes prior to taking the double-blind medication to help minimize flushing effects.

In Group A, the primary efficacy analysis was a comparison of the mean percent change in non-HDL levels between the SIMCOR 2000/20 mg and simvastatin 20 mg groups, and if statistically significant, then a comparison was conducted between the SIMCOR 1000/20 mg and simvastatin 20 mg groups. In Group B, the primary efficacy analysis was a determination of whether the mean percent change in non-HDL in the SIMCOR 2000/40 mg group was non-inferior to the mean percent change in the simvastatin 80 mg group, and if so, whether the mean percent change in non-HDL in the SIMCOR 1000/40 mg group was non-inferior to the mean percent change in the simvastatin 80 mg group.

In Group A, the non-HDL-C lowering with SIMCOR 2000/20 and SIMCOR 1000/20 was statistically significantly greater than that achieved with simvastatin 20 mg after 24 weeks (p<0.05; Table 4). The completion rate after 24 weeks was 72% for the SIMCOR arms and 88% for the simvastatin 20 mg arm. In Group B, the non-HDL-C lowering with SIMCOR 2000/40 and SIMCOR 1000/40 was non-inferior to that achieved with simvastatin 80 mg after 24 weeks (Table 5). The completion rate after 24 weeks was 78% for the SIMCOR arms and 80% for the simvastatin 80 mg arm.

SIMCOR was not superior to simvastatin in lowering LDL-C in either Group A or Group B. However, SIMCOR was superior to simvastatin in both groups in lowering TG and raising HDL (Tables 6 and 7).

Table 4. Non-HDL Treatment Response Following 24-Week Treatment Mean Percent Change from Simvastatin 20-mg Treated Baseline
Group A
Simcor 2000/20Simcor 1000/20Simvastatin 20
Weeknadose
(mg/mg)
non-HDLbnaDose
(mg/mg)
non-HDLbnaDose
(mg/mg)
non-HDLb
Baseline 56---163.1
mg/dL
108---164.8
mg/dL
102---163.7
mg/dL

a   n=number of subjects with values in the analysis window at each timepoint

b   The percent change from baseline is the model-based mean from a repeated measures mixed model with no imputation for missing data from study dropouts.

   significant vs. simvastatin 20 mg at the primary endpoint (Week 24), p<0.05

4 52500/20-12.9%86500/20-12.8%9120-8.3%
8461000/20-17.5%911000/20-15.5%9520-8.3%
12461500/20-18.9%901000/20-14.8%9620-6.4%
24402000/20-19.5%781000/20-13.6%9020-5.0%
Dropouts by week 24: 28.6%27.8%11.8%
Table 5. Non-HDL Treatment Response Following 24-Week Treatment Mean Percent Change from Simvastatin 40-mg Treated Baseline
Group B
Simcor 2000/40Simcor 1000/40Simvastatin 80
Weeknadose
(mg/mg)
non-HDLbnaDose
(mg/mg)
non-HDLbnaDose
(mg/mg)
non-HDLb
Baseline 98---144.4
mg/dL
111---141.2
mg/dL
113---134.5
mg/dL

a   n=number of subjects with values in the analysis window at each timepoint

b   The percent change from baseline is the model-based mean from a repeated measures mixed model with no imputation for missing data from study dropouts.

c   non-inferior to Simvastatin 80 arm; 95% confidence interval of mean difference in non-HDL for Simcor 2000/40 vs. Simvastatin 80 is (-7.7%, 4.5%)

d   non-inferior to Simvastatin 80 arm; 95% confidence interval of mean difference in non-HDL for Simcor 1000/40 vs. Simcor 80 is (-6.6%, 5.3%)

4 96500/40-6.0%108500/40-5.9%11080-11.3%
8931000/40-15.5%1001000/40-16.2%10480-13.7%
12901500/40-18.4%971000/40-12.6%10080-9.5%
24802000/40-7.6%c821000/40-6.7%d9080-6.0%
Dropouts by week 24: 18.4%26.1%20.4%
Table 6. Mean Percent Change from Baseline to Week 24 in Lipoprotein Lipid Levels
Treatment Group A
TREATMENT N LDL-C Total-C HDL-C TGa Apo B

*   either treatment naïve or after receiving simvastatin 20 mg

a   medians are reported for TG

Baseline
(mg/dL)*
26612020743209102
Simvastatin
20 mg
102-6.7%-4.5%7.8%-15.3%-5.6%
SIMCOR
1000/20
108-11.9%-8.8%20.7%-26.5%-13.2%
SIMCOR
2000/20
56-14.3%-11.1%29.0%-38.0%-18.5%
Table 7. Mean Percent Change from Baseline to Week 24 in Lipoprotein Lipid Levels
Treatment Group B
TREATMENT N LDL-C Total-C HDL-C TGa Apo B
Baseline
(mg/dL)*
3221081874714593
Simvastatin
80 mg
113-11.4%-6.2%0.1%0.3%-7.5%
SIMCOR
1000/40
111-7.1%-3.1%15.4%-22.8%-7.7%
SIMCOR
2000/40
98-5.1%-1.6%24.4%-31.8%-10.5%

*  after receiving simvastatin 40 mg

a   medians are reported for TG

Limitations of use

No incremental benefit of SIMCOR on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin monotherapy and niacin monotherapy has been established.

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