Advicor
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Advicor - Scientific Information

Manufacture: Sepracor Pharmaceuticals, Inc.
Country: Canada
Condition: High Cholesterol, High Cholesterol, Familial Heterozygous, Hyperlipoproteinemia Type IIb, Elevated LDL VLDL, Hyperlipoproteinemia Type IIa, Elevated LDL, Hyperlipoproteinemia
Class: Antihyperlipidemic combinations
Form: Tablets
Ingredients: niacin, lovastatin, FD&C yellow No 615 (750/20 tablet only), hydroxypropyl methylcellulose, iron oxide yellow (500/20 and 1000/20 tablets only), iron oxide red (500/20, 1000/20 and 1000/40 tablets only), iron oxide black (1000/20 tablet only), macrogol, povidone, polyethylene glycol, polysorbate 80 (500/20, 750/20 and 1000/20 tablets only), stearic acid, and titanium dioxide

Pharmaceutical information

Drug Substance

Proper name: niacin and lovastatin
Chemical name: Niacin: nicotinic acid or 3-pyridinecarboxylic acid
Lovastatin: [1S-[1 (alpha)(R*), 3(alpha), 7 (beta), 8 (beta)]]-1, 2, 3, 7, 8, 8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl]-1-naphthalenyl 2-methylbutanoate
Molecular formula and molecular mass: Niacin: C6H5NO2, 123.11
Lovastatin: C24H36O5, 404.55
Structural formula:
Niacin:


Lovastatin:


Physicochemical properties: Niacin: White, nonhygroscopic crystalline powder; very soluble in boiling water, boiling ethanol, and propylene glycol; insoluble in ethyl ether. Sparingly soluble in water at 20°C.
Lovastatin: White, nonhygroscopic crystalline powder; insoluble in water; sparingly soluble in ethanol, methanol, and acetonitrile.

Clinical Trials

No mortality and morbidity studies have been conducted with ADVICOR.

Double-Blind Study

In a multi-center, randomized, double-blind, parallel, 28-week, active-comparator study in patients with Type IIa and IIb hyperlipidaemia, ADVICOR was compared to each of its components (NIASPAN and lovastatin). Using a forced dose-escalation study design, patients received each dose for at least 4 weeks. Patients randomized to treatment with ADVICOR initially received 500/20 mg. The dose was increased at 4-week intervals to a maximum of 1000/20 mg in one-half of the patients and 2000/40 mg in the other half. The NIASPAN monotherapy group underwent a similar titration from 500 mg to 2000 mg. The patients randomized to lovastatin monotherapy received 20 mg for 12 weeks titrated to 40 mg for up to 16 weeks. Up to a third of the patients randomized to ADVICOR or NIASPAN discontinued prior to Week 28. ADVICOR decreased LDL-C, TG and Lp(a) and increased HDL-C, see tables 4, 5, 6 and 7 below.

  1. LDL-lowering with ADVICOR was significantly greater than that achieved with lovastatin 40 mg only after 28 weeks of titration to a dose of 2000 mg/40 mg (p<0.0001);
  2. ADVICOR in doses of 1000/20 mg achieved greater LDL-lowering than 1000 mg NIASPAN alone (p<0.0001).

The LDL-C results are summarized in Table 1.

TABLE 1: LDL-C Mean Percent Change from Baseline
Week ADVICOR NIASPAN lovastatin
n* Dose
(mg/mg)
LDL n* Dose
(mg)
LDL n* Dose
(mg)
LDL
Baseline 57 - 190.9 mg/dL 61 - 189.7 mg/dL 61 - 185.6 mg/dL
12 47 1000/20 -30% 46 1000 -3% 56 20 -29%
16 47 1000/40 -36% 44 1000 -6% 56 40 -31%
20 42 1500/40 -37% 43 1500 -12% 54 40 -34%
28 42 2000/40 -42% 41 2000 -14% 53 40 -32%

*n = number of patients remaining in the trial at each timepoint

ADVICOR achieved significantly greater HDLC-raising compared to lovastatin and NIASPAN monotherapy at all doses (Table 2).

TABLE 2: HDL-C Mean Percent Change from Baseline
Week ADVICOR NIASPAN lovastatin
n* Dose
(mg/mg)
HDL n* Dose
(mg)
HDL n* Dose
(mg)
HDL
Baseline 57 - 45 mg/dL 61 - 47 mg/dL 61 - 43 mg/dL
12 47 1000/20 +20% 46 1000 +14% 56 20 +3%
16 45 1000/40 +20% 44 1000 +15% 56 40 +5%
20 42 1500/40 +27% 43 1500 +22% 54 40 +6%
28 42 2000/40 +30% 41 2000 +24% 53 40 +6%

*n = number of patients remaining in the trial at each timepoint

In addition, ADVICOR achieved significantly greater TG-lowering at doses of 1000/20 mg or greater compared to lovastatin and NIASPAN monotherapy (Table 3).

TABLE 3: TG Median Percent Change from Baseline
Week ADVICOR NIASPAN lovastatin
n* Dose
(mg/mg)
TG n* Dose
(mg)
TG n* Dose
(mg)
TG
Baseline 57 - 174 mg/dL 61 - 186 mg/dL 61 - 171 mg/dL
12 47 1000/20 -32% 46 1000 -22% 56 20 -20%
16 45 1000/40 -39% 44 1000 -23% 56 40 -17%
20 42 1500/40 -44% 43 1500 -31% 54 40 -21%
28 42 2000/40 -44% 41 2000 -31% 53 40 -20%

*n = number of patients remaining in the trial at each timepoint

The Lp(a) lowering effects of ADVICOR and NIASPAN were similar, and both were superior to lovastatin (Table 4). The independent effect of lowering Lp(a) with NIASPAN or ADVICOR on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

TABLE 4: Lp(a) Median Percent Change from Baseline
Week ADVICOR NIASPAN lovastatin
n* Dose
(mg/mg)
Lp(a) n* Dose
(mg)
Lp(a) n* Dose
(mg)
Lp(a)
Baseline 57 - 34 mg/dL 61 - 41 mg/dL 61 - 42 mg/dL
12 47 1000/20 -9% 46 1000 -8% 55 20 +8%
16 45 1000/40 -9% 44 1000 -12% 55 40 +8%
20 42 1500/40 -17% 43 1500 -22% 53 40 +6%
28 42 2000/40 -22% 41 2000 -32% 52 40 0%

*n = number of patients remaining in the trial at each timepoint

ADVICOR demonstrated a mean TC:HDL-C change from –27.4% at 500/20 mg to –45.4% at 2000/40 mg. The TC:HDL-C ratio response was significantly greater than the response to lovastatin alone (-28.8%).

Detailed Pharmacology

This section details the pharmacology of ADVICOR’s individual components, niacin and lovastatin.

Human Pharmacology

Niacin

Pharmacodynamics

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.

Pharmacokinetics

A total of fifteen open-label studies were conducted to investigate the bioavailability and pharmacokinetics of NIASPAN (niacin) (equivalent to extended-release niacin contained in ADVICOR) 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 Nmethyl-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.

Lovastatin

Pharmacodynamics

In patients with hypercholesterolemia, lovastatin has been shown to reduce total cholesterol, LDL-C and triglycerides, and increase HDL-C. Maximum therapeutic response can be seen in 4-6 weeks of treatment. The effects of lovastatin induced changes in the lipoprotein levels, including reduction of serum cholesterol, on cardiovascular morbidity and mortality has not been established.

Animal Pharmacology

Niacin

Pharmacodynamics

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.

Pharmacokinetics

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 μg/mL and 103 minutes, for 500 mg niacin in the oral solution were 86 μg/mL and 37 minutes, and for 187 mg niacin in the iv infusion were 5.3 μg/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.

Lovastatin

Pharmacodynamics

Lovastatin inhibits cholesterol synthesis in vitro in enzyme assays and cell culture assays, and reduces total cholesterol and triglycerides in vivo. In animal studies cholesterol reduction was dose dependent during four weeks of treatment.

Pharmacokinetics

Lovastatin is rapidly absorbed after oral administration of DMSO/saline solution or capsule, with about 45% and 23% of the dose absorbed in the rat and dog, respectively.

In rat and dog, lovastatin is rapidly removed from blood, is concentrated in the lover and absorption/excretion tissues, and is rapidly eliminated from the body. In rat, dog, monkey and man, lovastatin is about 95% bound to plasma proteins. Brain uptake was shown to be linear in the rat. No lovastatin was found in aqueous humour or cerebrospinal fluid of dog.

Metabolism has been investigated in mouse, rat and dog. Lovastatin is a lactone which is readily hydrolyzed in vivo to the corresponding β-hydroxy acid (lovastatin acid), which is the main active metabolite. The lactone and acid are in equilibrium. Lovastatin undergoes extensive firstpass extraction in the liver and excretion in bile. Thus, little active drug reaches the general circulation. In mouse and rat following intravenous administration of hydroxy acid (HA), the main metabolites in bile were 3'-hydroxy and taurine conjugates. Some 3'-hydroxy-iso-HA and 6'-exomethylene HA were also found in rat. In the dog, following oral administration of lovastatin, the main metabolites in plasma were lovastatin (as the β-hydroxy acid), and the 6'-β-hydroxymethyl, 6'-exomethylene and 6'-β-hydroxyl analogues. Metabolites in bile included 3'-hydroxy-iso-HA. Seven metabolites were found in dog urine, with identical retention times to 7 metabolites found in human urine.

In all species examined, biliary excretion is the major route of elimination, with 78-98% excreted in feces as active and inactivated metabolites following oral administration, and less than 4% excreted in urine as inactive metabolites.

Toxicology

Niacin

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.

Lovastatin

The acute LD50 by the oral route is greater than 20 g/kg and 5 g/kg in mice and rats, respectively. These doses are vastly in excess of the maximum recommended human therapeutic dose of 80 mg per day.

A marked increase in the lethal and hepatotoxic effects of lovastatin following daily administration of the compound to mice fed on a high cholesterol diet has been reported.

The rabbit was reported to be markedly more sensitive than rodents to the lethal and hepatotoxic effects of lovastatin with mortality occurring within a few days of repeated administration of 100 mg/kg/day. Plasma levels of lovastatin were at least one order of magnitude higher than those in other species although the severity of toxic effects was not related to plasma or hepatic concentrations.

In a multiple dose level study (5, 30, 180 mg/kg/day) in dogs, performed following completion of a nine week pilot study at a single dose level of 180 mg/kg/day, the only notable effect appeared to be a 50% decrease in total serum cholesterol. One high dose (180 mg/kg/day) male died following a tonic convulsion at week 13 of dosing. Histopathological examination showed CNS lesions (vascular degeneration with endothelial hyperplasia, perivascular oedema and multifocal haemorrhage). Optic changes were noted in two other high dose animals (one cataract and one opaque plaque of the posterior capsule).

In mice, hepatic carcinomas and adenomas were seen at 500 mg/kg/day particularly in male animals. A significant increase in the incidence of acanthosis and papillomas in the nonglandular portion of the stomach was seen in both sexes at 500 mg/kg/day. Pulmonary adenomas were also noted in females although the incidence was similar to historical controls.

In rats, a significant increase in hepatic carcinomas was seen in males at 24 months. However, the incidence was similar to that found in controls sacrificed at interim stages of the study and to that observed spontaneously in the same strain of rat.

In both mouse and rat studies the highest doses tested were approximately 300 and 100 times greater respectively than the maximum recommended dose in man on a mg/kg bw basis.

ADVICOR

Based on the results of a 4-week oral toxicity study in dogs dosed by oral gavage, treatment for 28 days at $900/36 mg/kg caused emesis, edema of the eyelids, excessive salivation, decreased serum cholesterol and triglyceride levels, and minimal hepatocellular hypertrophy, and in females also a body weight loss. Emesis, edema of the eyelids and decrease in cholesterol level were also seen at 300/12 mg/kg, but with lower incidence and lower severity. The No Observed Effect Level (NOEL) was <100/4 mg/kg. The No Observed Adverse Effect Level (NOAEL) was 300/12 mg/kg.