Niaspan - Scientific Information
|Manufacture:||Sunovion Pharmaceuticals Inc.|
|Condition:||High Cholesterol, Hyperlipoproteinemia Type V, Elevated Chylomicrons VLDL, Hyperlipoproteinemia Type IV, Elevated VLDL, Hyperlipoproteinemia|
|Class:||Miscellaneous antihyperlipidemic agents, Vitamins|
|Ingredients:||extended-release niacin, methylcellulose, povidone, stearic acid|
|Proper name:||Niacin or nicotinic acid|
|Chemical name:||3-pyridinecarboxylic acid|
|Molecular formula and molecular mass:||C6H5NO2 M.W. = 123.11|
|Physicochemical properties:||Niacin is a white, crystalline powder, very soluble in water|
NIASPAN has not been shown to reduce cardiovascular morbidity or mortality among patients already treated with a statin.
NIASPAN (extended-release niacin) has been shown to effectively modify atherogenic dyslipidaemia by lowering LDL-C and apolipoprotien B, triglycerides and Lp(a), increasing HDL-C, and transforming small dense LDL into normal sized LDL. Three pivotal, placebo- controlled studies were conducted to establish the efficacy and safety of NIASPAN (extended- release niacin) dosed once daily at bedtime. A dose-ranging study was conducted comparing NIASPAN 1000 mg, 2000 mg and placebo. Another study was conducted to compare NIASPAN 1500 mg to immediate-release (IR) niacin 1500 and 3000 mg/day and to placebo. The third pivotal study was a dose-escalation study. The primary efficacy endpoints were percent change from baseline in low-density lipoprotein cholesterol (LDL C) and Apolipoprotein B (Apo B). The secondary endpoints included percent change from baseline in high-density lipoprotein cholesterol (HDL-C), Lipoprotein (a) [Lp(a)], and triglycerides (TG).
Reductions in LDL-C, Apo B, triglycerides, and Lp(a), as well as elevations in HDL-C, were comparable to those seen with equivalent daily doses of IR niacin.
Pooled results for three placebo-controlled studies are provided in Table 1 below.
|Placebo||500 mg||1000 mg||1500 mg||2000 mg|
|LDL-C||0.12 ± 1.05||-3.2 ± 1.32||-7.6 ± 1.08*||-13.3 ± 1.21*||-15.8 ± 1.49*|
|Apo B||0.18 ± 1.02||-2.4 ± 1.12||-6.8 ± 1.00*||-13.4 ± 1.07*||-16.1 ± 1.35*|
|TC||0.64 ± 0.85||-1.9 ± 1.05||-4.5 ± 0.82*||-9.1 ± 0.87*||-11.5 ± 1.04*|
|HDL-C||3.4 ± 1.00||9.6 ± 1.44*||16.3 ± 1.33*||20.9 ± 1.76*||24.3 ± 2.12*|
|TG||4.6 ± 3.11||-5.4 ± 2.91*||-14.2 ± 2.88*||-20.6 ± 2.82*||-32.2 ± 2.56*|
|TC/HDL-C||-2.0 ± 1.06||- 10.0 ± 1.07*||-17.1 ± 1.12*||-22.9 ± 1.44*||-27.4 ± 1.44*|
|Lp(a)||0.0 ± 2.98||-3.4 ± 2.19||-12.3 ± 2.22*||-17.3 ± 2.36*||-25.0 ± 2.21*|
* ANOVA comparing treatment to corresponding placebo values; statistically significant at p#0.01
Clinical data indicate that in patients with primary hypercholesterolemia and mixed dyslipidaemia treated with NIASPAN, the changes in lipid concentrations are greater for women than for men.
Niacin functions in the body after conversion to NAD in the NAD coenzyme system. Niacin is a potent vasodilator, probably acting directly on vascular smooth muscle of the face and trunk. In gram doses, niacin reduces TC, LDL-C and TG and increases HDL-C. Reductions in VLDL-C and Lp(a) are also seen, and clinical data suggest a favourable effect on the small dense LDL particle phenotype ("pattern B") associated with increased CHD risk. The magnitude of individual effects varies with the underlying hyperlipidaemic condition.
The exact mechanisms by which niacin exerts its effects are not clearly understood, but appear to be diverse. The rates of hepatic synthesis of LDL and VLDL are decreased, for example, as are serum levels of Apo B, while enhanced clearance of VLDL may also occur, possibly due to increased lipoprotein lipase activity. The decreased production of VLDL is thought to result from transient inhibition of lipolysis and from decreases in the delivery of free fatty acids to the liver, in TG synthesis and in VLDL-triglyceride transport. The lowered LDL levels may then result from decreased VLDL production and enhanced hepatic clearance of LDL precursors.
The increase in HDL-C resulting from niacin treatment is associated with a shift in distribution of subfractions, with increases in the proportion of HDL2 relative to HDL3 and in Apo A-I respectively. Niacin is not known to affect either the rate of cholesterol synthesis, or the faecal excretion of fats, sterols or bile acids.
A total of fifteen open-label studies were conducted to investigate the bioavailability and pharmacokinetics of NIASPAN (extended-release niacin) in humans. Of these, twelve were single-dose, two were multiple dose and one was a dose-rate escalation study.
NIASPAN is well absorbed: approximately 89 to 95% is absorbed relative to immediate-release (IR) niacin based on total urine recovery data. Peak plasma niacin concentrations occur 4 to 5 hours after single- or multiple-dose NIASPAN administration.
The rate of niacin absorption appears to affect the metabolic profile: after single doses, plasma concentrations and urine recovery of niacin and nicotinuric acid are higher for IR niacin than for NIASPAN while plasma concentrations and urine recovery of N-methylnicotinamide and N- methyl-2-pyridone-5-carboxamide are lower.
Once-daily administration of NIASPAN in the dose range 1000 mg to 3000 mg for six days resulted in nonlinear accumulation of niacin in plasma. Plasma concentrations of nicotinuric acid also accumulated in a nonlinear fashion for NIASPAN 1000 to 2000 mg doses, but nicotinuric acid formation appeared to be saturated at the 3000 mg dose, based on dose-corrected AUC comparisons. Plasma N-methylnicotinamide appeared to be dose-proportional in the 1000 to 2000 mg dose range, but plasma data suggested MNA formation became saturated above 2000 mg; dose-corrected Cmax and AUC decreased with rising niacin dose through 3000 mg.
Niacin and its major metabolites are eliminated in the urine. After single or multiple doses of 1000 mg to 2000 mg NIASPAN, approximately 60 to 75% of the dose is recovered in urine as niacin, nicotinuric acid, N-methylnicotinamide and N-methyl-2-pyridone-5-carboxamide. Less than 3% of a single 1500 mg NIASPAN dose is recovered as unchanged niacin in urine. Under steady-state conditions, the proportion of niacin recovered unchanged increases with increasing NIASPAN doses from 1000 to 3000 mg. Steady-state recovery of nicotinuric acid increases with increasing NIASPAN doses from 1000 to 2000 mg; the proportion recovered is similar for 2000 and 3000 mg doses. Steady-state recovery of N-methylnicotinamide is relatively consistent across this dose range, while the proportion recovered as N-methyl-2-pyridone-5-carboxamide decreases with increasing NIASPAN dose.
A number of pharmacodynamic studies have been performed using laboratory animal models, demonstrating the effect of niacin on plasma free-fatty acids. In dog studies, reductions were observed in free fatty acid uptake by the hearts of adult dogs, which were intravenously infused with 2.4 mol niacin/ kg body weight/minute for 30 minutes before coronary occlusion and throughout a 15 minute occlusion period. Improvements in myocardial function and subendocardial blood flow were attributed to the effect of niacin on free-fatty acid uptake. A similar experiment was performed using isolated pig hearts in situ. A reduction in free-fatty acid accumulation was observed after niacin administration. Cardioprotective effects of niacin were shown by decreased release of creatine kinase, and improved coronary blood flow and cardiac contractility.
The plasma free-fatty acid levels in dogs intravenously dosed with 1 to 32 mg/kg of niacin initially decreased in another study, followed by a rebound elevation to plasma levels greater than baseline, in a dose-related fashion. A similar biphasic effect was seen in rats intravenously dosed at 10 mg/kg. The free-fatty acid rebound mechanism was ascribed to a primary role of the pituitary-adrenal system, since the free-fatty acid rebound in rats was paralleled by an increase in plasma corticosterone levels after niacin administration. A further study showed that niacin blocked the norepinephrine effect on plasma-free fatty acid release in dogs when administered intravenously over one hour at a relatively high dose of 100 mg/kg.
In a cross-over bioavailability study, beagle dogs were dosed once with 500 mg niacin as the NIASPAN modified-release tablet, once with 500 mg niacin as an oral solution, and once with 187 mg niacin as an iv infusion over three hours. Analysis of plasma for concentrations of niacin and nicotinuric acid were made over suitable time periods (eight hours for the oral doses and four hours for the iv infusion). Nicotinuric acid was found to be a minor metabolite in plasma. The mean plasma niacin Cmax and Tmax for 500 mg niacin in NIASPAN were 8.9 g/mL and 103 minutes, for 500 mg niacin in the oral solution were 86 g/mL and 37 minutes, and for 187 mg niacin in the iv. infusion were 5.3 g/mL and 103 minutes. The absolute bioavailability of the NIASPAN extended-release formulation was 89%, and absolute bioavailability of the oral solution was approximately 558%, compared to the iv infusion. No adverse effects were observed in the treated dogs from any of the treatment groups.
Metabolism data for laboratory animals from the literature reviewed demonstrate that niacin and nicotinamide are extensively metabolised at levels found endogenously, at therapeutic dose levels (lipid regulating) and higher dose levels. At very high doses, niacin metabolism is saturated.
Niacin has been shown to be of low acute toxicity in rats, mice and dogs, when administered via oral and parenteral routes. The LD50 for niacin was 5 to 7 g/kg in rats and mice after oral dosing. Dogs tolerated 2 g/kg without adverse effects. At very high lethal or non-lethal doses, signs of toxicity in rodents included cyanosis, slowed respiration, ataxia and clonic convulsions.
In repeat dose studies with rats and dogs, no signs of toxicity were noted at 1g/kg, and 100 mg/kg per day respectively.
Mice administered daily doses, equivalent to approximately 4.1 g/kg per day for females and 5.4 g/kg per day for male, in their drinking water from six weeks of age throughout the remainder of their lives showed no treatment-related carcinogenic effects and no effects on survival rates.
Female rabbits have been dosed with 0.3 g niacin per day from pre-conception to lactation, and gave birth to offspring without teratogenic effects.