Mechanism of Action
Lovastatin is a lactone that is readily hydrolyzed in vivo to the corresponding
β-hydroxyacid, a potent inhibitor of HMG-CoA reductase, the enzyme that catalyzes
the conversion of HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate
is an early step in the biosynthetic pathway for cholesterol.
The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological and clinical studies have established that high LDL-C and low high-density lipoprotein cholesterol (HDL-C) levels are both associated with coronary heart disease. However, the risk of developing coronary heart disease is continuous and graded over the range of cholesterol levels and many coronary events do occur in patients with total cholesterol (Total-C) and LDL-C levels in the lower end of this range.
ALTOCOR™ (lovastatin extended-release tablets) has been shown to reduce LDL-C, and Total-C. Across all doses
studied, treatment with ALTOCOR™ (lovastatin extended-release tablets) has been shown to result in variable
reductions in triglycerides (TG), and variable increases in HDL-C (see Table
III under Clinical Studies).
Lovastatin immediate-release tablets have been shown to reduce both normal
and elevated LDL-C concentrations. LDL is formed from very low-density lipoprotein
(VLDL) and is catabolized predominantly by the high-affinity LDL receptor. The
mechanism of the LDL-lowering effect of lovastatin immediate-release may involve
both reduction of VLDL-C concentration, and induction of the LDL receptor, leading
to reduced production and/or increased catabolism of LDL-C. Apolipoprotein B
(Apo B) also falls substantially during treatment with lovastatin immediate-release.
Since each LDL particle contains one molecule of Apo B, and since little Apo
B is found in other lipoproteins, this strongly suggests that lovastatin immediate-release
does not merely cause cholesterol to be lost from LDL, but also reduces the
concentration of circulating LDL particles. In addition, lovastatin immediate-release
can produce increases of variable magnitude in HDL-C, and modestly reduces VLDL-C
and plasma TG (see Table IV under Clinical Studies). The independent
effect of raising HDL or lowering TG on the risk of coronary and cardiovascular
morbidity and mortality has not been determined. The effects of lovastatin immediate-release
on lipoprotein (a) [Lp(a)], fibrinogen, and certain other independent biochemical
risk markers for coronary heart disease are unknown.
Lovastatin, as well as some of its metabolites, are pharmacologically active
in humans. The liver is the primary site of action and the principal site of
cholesterol synthesis and LDL clearance (see DOSAGE AND ADMINISTRATION)
Pharmacokinetics and Drug Metabolism
The appearance of lovastatin in plasma from an ALTOCOR (lovastatin extended-release tablets) ™ Extended-Release Tablet is slower and more prolonged compared to the lovastatin immediate-release formulation.
A pharmacokinetic study carried out with ALTOCOR™ involved measurement
of the systemic concentrations of lovastatin (pro-drug), lovastatin acid (active-drug)
and total and active inhibitors of HMG-CoA reductase. The pharmacokinetic parameters
in 12 hypercholesterolemic subjects at steady state, after 28 days of treatment,
comparing ALTOCOR™ 40 mg to lovastatin immediate-release 40 mg, are summarized
in Table I.
Table I: ALTOCOR™ vs Lovastatin Immediate-Release (IR) (Steady-State
Pharmacokinetic Parameters at Day 28)
|| Cmax (ng/mL )
|| Cmin (ng/mL)
|| Tmax (h)
|| AUC 0-24hr
| ALTOCOR™ 40 mg*
| Lovastatin IR 40 mg**
|L=lovastatin, LA=lovastatin acid, TI=total
inhibitors of HMG-CoA reductase, AI=active inhibitors of HMG-CoA reductase,
Cmax=highest observed plasma concentration, Cmin=trough concentration
at t=24 hours after dosing, Tmax=time at which the Cmax occurred, AUC0-24hr=area
under the plasma concentration-time curve from time 0 to 24 hr after dosing,
calculated by the linear trapezoidal rule.
* Administered at bedtime
** Administered with the evening meal.
The mean plasma concentration-time profiles of lovastatin and lovastatin acid
in patients after multiple doses of ALTOCOR™ or lovastatin immediate-release
at day 28 are shown in Figure 1.
Figure 1: Mean (SD) plasma concentration-time profiles of
lovastatin and lovastatin acid in hypercholesterolemic patients (n=12) after
28 days of administration of ALTOCOR™ or lovastatin immediate release
The extended-release properties of ALTOCOR™ (lovastatin extended-release tablets) are characterized by a prolonged absorptive phase, which results in a longer Tmax and lower Cmax for lovastatin (prodrug) and its major metabolite, lovastatin acid, compared to lovastatin immediate-release.
The bioavailability of lovastatin (pro-drug) as measured by the AUC0-24hr
was greater for ALTOCOR™ compared to lovastatin immediate-release (as
measured by a chemical assay), while the bioavailability of total and active
inhibitors of HMG-CoA reductase were equivalent to lovastatin immediate-release
(as measured by an enzymatic assay).
With once-a-day dosing, mean values of AUCs of active and total inhibitors at steady state were about 1.8 -1.9 times those following a single dose. Accumulation ratio of lovastatin exposure was 1.5 after multiple daily doses of ALTOCOR™ (lovastatin extended-release tablets) compared to that of a single dose measured using a chemical assay.
ALTOCOR™ (lovastatin extended-release tablets) appears to have dose linearity for doses from 10 mg up to 60 mg per day.
When ALTOCOR™ was given after a meal, plasma concentrations of lovastatin
and lovastatin acid were about 0.5 - 0.6 times those found when ALTOCOR™ (lovastatin extended-release tablets)
was administered in the fasting state, indicating that food decreases the bioavailability
of ALTOCOR™ (lovastatin extended-release tablets) . There was an association between the bioavailability of
ALTOCOR™ (lovastatin extended-release tablets) and dosing after mealtimes. Bioavailability was lowered under
the following conditions, (from higher bioavailability to lower bioavailability)
in the following order: under overnight fasting conditions, before bedtime,
with dinner, and with a high fat breakfast. In a multicenter, randomized, parallel
group study, patients were administered 40 mg of ALTOCOR™ (lovastatin extended-release tablets) at three different
times; before breakfast, after dinner and at bedtime. Although there was no
statistical difference in the extent of lipid change between the three groups,
there was a numerically greater reduction in LDL-C and TG and an increase in
HDL-C when ALTOCOR™ (lovastatin extended-release tablets) was administered at bedtime. Results of this study
are displayed in Table II.
Table II: ALTOCOR™ (lovastatin extended-release tablets) 40 mg (Least Squares Mean Percent
Changes from Baseline to Endpoint at 4 weeks of treatment*)
| Before Breakfast
| After Dinner
| Before Bedtime
|N=22 for the Before Breakfast group, N=23 for the After Dinner
group, and N=23 for the Before Bedtime group.
*All changes from baseline are statistically significant.
At steady state in humans, the bioavailability of lovastatin, following the
administration of ALTOCOR™, was 190% compared to lovastatin immediate-release.
Absorption of lovastatin, estimated relative to an intravenous reference dose
in each of four animal species tested, averaged about 30% of an oral dose. Following
an oral dose of 14C-labeled lovastatin in man, 10% of the dose was
excreted in urine and 83% in feces. The latter represents absorbed drug equivalents
excreted in bile, as well as any unabsorbed drug. In a single dose study in
four hypercholesterolemic patients, it was estimated that less than 5% of an
oral dose of lovastatin reaches the general circulation as active inhibitors.
Both lovastatin and its β-hydroxyacid metabolite are highly bound ( > 95%) to human plasma proteins. Animal studies demonstrated that lovastatin crosses the blood-brain and placental barriers.
In animal studies, after oral dosing, lovastatin had high selectivity for the liver, where it achieved substantially higher concentrations than in non-target tissues.
Lovastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. As a consequence of extensive hepatic extraction of lovastatin, the availability of drug to the general circulation is low and variable.
Metabolism studies with ALTOCOR™ have not been conducted.
Lovastatin is a lactone that is readily hydrolyzed in vivo to the corresponding
β-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA
reductase is the basis for an assay in pharmacokinetic studies of the β-hydroxyacid
metabolites (active inhibitors) and, following base hydrolysis, active plus
latent inhibitors (total inhibitors) in plasma following administration of lovastatin.
The major active metabolites present in human plasma are the β-hydroxyacid of lovastatin, its 6'-hydroxy derivative, and two additional metabolites.
The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory
activity in plasma. Potent inhibitors of CYP3A4 can raise the plasma levels
of HMG-CoA reductase inhibitory activity and increase the risk of myopathy (see
WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS:
Lovastatin is a substrate for CYP3A4 (see PRECAUTIONS: DRUG
INTERACTIONS). Grapefruit juice contains one or more components that
inhibit CYP3 A4 and can increase the plasma concentrations of drugs metabolized
by CYP3A4. In one study,1 10 subjects consumed 200 mL of double-strength
grapefruit juice (one can of frozen concentrate diluted with one rather than
3 cans of water) three times daily for 2 days and an additional 200 mL double-strength
grapefruit juice together with and 30 and 90 minutes following a single dose
of 80 mg lovastatin on the third day. This regimen of grapefruit juice resulted
in mean increases in the concentration of lovastatin and its beta-hydroxyacid
metabolite (as measured by the area under the concentration-time curve) of 15-fold
and 5-fold respectively (as measured using a chemical assay - liquid chromatography/tandem
mass spectrometry). In a second study, 15 subjects consumed one 8 oz glass of
single-strength grapefruit juice (one can of frozen concentrate diluted with
3 cans of water) with breakfast for 3 consecutive days and a single dose of
40 mg lovastatin in the evening of the third day. This regimen of grapefruit
juice resulted in a mean increase in the plasma concentration (as measured by
the area under the concentration-time curve) of active and total HMG-CoA reductase
inhibitory activity [using a validated enzyme inhibition assay different from
that used in the first study, both before (for active inhibitors) and after
(for total inhibitors) base hydrolysis] of 1.34-fold and 1.36-fold, respectively,
and of lovastatin and its β-hydroxyacid metabolite (measured using a chemical
assay - liquid chromatography/tandem mass spectrometry) of 1.94-fold and 1.57-fold,
respectively. The effect of amounts of grapefruit juice between those used in
these two studies on lovastatin pharmacokinetics has not been studied.
ALTOCOR (lovastatin extended-release tablets) ™
In a single-dose study with ALTOCOR™, the amounts of lovastatin and lovastatin
acid excreted in the urine were below the lower limit of quantitation of the
assay (1.0 ng/mL), indicating that negligible excretion of ALTOCOR™ occurs
through the kidney.
Lovastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile.
In a study with lovastatin immediate-release which included 16 elderly patients
between 70-78 years of age who received lovastatin immediate-release 80 mg/day,
the mean plasma level of HMG-CoA reductase inhibitory activity was increased
approximately 45% compared with 18 patients between 18-30 years of age (see
PRECAUTIONS, Geriatric Use)
Pharmacokinetic data in the pediatric population are not available.
In a single dose pharmacokinetic study with ALTOCOR™ (lovastatin extended-release tablets) , there were no statistically
significant differences in pharmacokinetic parameters between men (n=12) and
women (n=10), although exposure tended to be higher in men than women.
In clinical studies with ALTOCOR™ (lovastatin extended-release tablets) , there was no clinically significant
difference in LDL-C reduction between men and women.
In a study of patients with severe renal insufficiency (creatinine clearance 10-30 mL/min), the plasma concentrations of total inhibitors after a single dose of lovastatin were approximately two-fold higher than those in healthy volunteers.
The effect of hemodialysis on plasma levels of lovastatin and its metabolites have not been studied.
No pharmacokinetic studies with ALTOCOR™ (lovastatin extended-release tablets) have been conducted in patients with hepatic insufficiency.
ALTOCOR™ (lovastatin extended-release tablets)
ALTOCOR™ (lovastatin extended-release tablets) has been shown to reduce Total-C, LDL-C, and TG and increase HDL-C in patients with hypercholesterolemia. Near maximal response was observed after four weeks of treatment and the response was maintained with continuation of therapy for up to 6 months.
In a 12-week, multicenter, placebo-controlled, double-blind, dose-response study in adult men and women 21 to 70 years of age with primary hypercholesterolemia, once daily administration of ALTOCOR™ (lovastatin extended-release tablets) 10 to 60 mg in the evening was compared to placebo. ALTOCOR™ (lovastatin extended-release tablets) produced dose related reductions in LDL-C and Total-C. ALTOCOR™ (lovastatin extended-release tablets) produced mean reductions in TG across all doses that varied from approximately 10% to 25%. ALTOCOR™ (lovastatin extended-release tablets) produced mean increases in HDL-C across all doses that varied from approximately 9% to 13%.
The lipid changes with ALTOCOR™ (lovastatin extended-release tablets) treatment in this study, from baseline
to endpoint, are displayed in Table III.
Table III: ALTOCOR™ (lovastatin extended-release tablets) vs. Placebo (Mean Percent Change from
Baseline After 12 Weeks)*
| ALTOCOR™ 10 mg
| ALTOCOR™ 20 mg
| ALTOCOR™ 40 mg
| ALTOCOR™ 60 mg
|N= the number of patients with values at both baseline and
*Except for the HDL-C elevation with ALTOCOR™ (lovastatin extended-release tablets) 10 mg, all lipid changes
with ALTOCOR™ (lovastatin extended-release tablets) were statistically significant compared to placebo.
**For LDL-C, 33 patients had values at baseline and endpoint.
The range of LDL-C responses is represented graphically in the following figure
Figure 2: ALTOCOR™ (lovastatin extended-release tablets) vs Placebo LDL-C Percent Change
from Baseline After 12 Weeks
The distribution of LDL-C responses is represented graphically by the boxplots
in Figure 2. The bottom line of the box represents the 25th percentile
and the top line, the 75th percentile. The horizontal line in the box represents
the median and the gray area is the 95% confidence interval for the median.
The range of responses is depicted by the tails and outliers.
ALTOCOR™ (lovastatin extended-release tablets) Long-Term Study
A total of 365 patients were enrolled in an extension study in which all patients were administered ALTOCOR™ (lovastatin extended-release tablets) 40 mg or 60 mg once daily for up to 6 months of treatment. The lipid-altering effects of ALTOCOR™ (lovastatin extended-release tablets) were comparable to what was observed in the dose-response study, and were maintained for up to 6 months of treatment.
In clinical studies with ALTOCOR™ (lovastatin extended-release tablets) , there were no statistically significant
differences in LDL-C reduction in an older population ( ≥ 65 years old), compared
to a younger population ( < 65 years old). There were also no statistically
significant differences in LDL-C reduction between male and female patients.
Lovastatin immediate-release has been shown to be effective in reducing Total-C and LDL-C in heterozygous familial and non-familial forms of primary hypercholesterolemia and in mixed hyperlipidemia. A marked response was seen within 2 weeks, and the maximum therapeutic response occurred within 4-6 weeks. The response was maintained during continuation of therapy. Single daily doses given in the evening were more effective than the same dose given in the morning, perhaps because cholesterol is synthesized mainly at night.
Lovastatin immediate-release was studied in controlled trials in hypercholesterolemic patients with well-controlled non-insulin dependent diabetes mellitus with normal renal function. The effect of lovastatin immediate-release on lipids and lipoproteins and the safety profile of lovastatin immediate-release were similar to that demonstrated in studies in nondiabetics. Lovastatin immediate-release had no clinically important effect on glycemic control or on the dose requirement of oral hypoglycemic agents.
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
Lovastatin immediate-release was compared to placebo in 8,245 patients with
hypercholesterolemia [Total-C 240-300 mg/dL (6.2 mmol/L-7.6 mmol/L), LDL-C > 160
mg/dL (4.1 mmol/L)] in the randomized, double-blind, parallel, 48-week EXCEL
study. All changes in the lipid measurements (see Table IV) observed
in lovastatin immediate-release-treated patients were dose-related and significantly
different from placebo (p ≤ 0.001). These results were sustained throughout
TABLE IV: Lovastatin Immediate-Release (IR) vs. Placebo (Percent
Change from Baseline - Average Values Between Weeks 12 and 48)
| LDL-C/ HDL-C
| 20 mg q.p.m.
| 40 mg q.p.m.
| 20 mg b.i.d.
| 40 mg b.i.d.
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a double-blind, randomized, placebo-controlled, primary prevention study, demonstrated that treatment with lovastatin immediate-release decreased the rate of acute major coronary events (composite endpoint of myocardial infarction, unstable angina, and sudden cardiac death) compared with placebo during a median of 5.1 years of follow-up. Participants were middle-aged and elderly men (ages 45-73) and women (ages 55-73) without symptomatic cardiovascular disease with average to moderately elevated Total-C and LDL-C, below average HDL-C, and who were at high risk based on elevated Total-C/HDL-C. In addition to age, 63% of the participants had at least one other risk factor (baseline HDL-C < 35 mg/dL, hypertension, family history, smoking and diabetes).
AFCAPS/TexCAPS enrolled 6,605 participants (5,608 men, 997 women) based on the following lipid entry criteria: Total-C range of 180-264 mg/dL, LDL-C range of 130-190 mg/dL, HDL-C of ≤ 45 mg/dL for men and ≤ 47 mg/dL for women, and TG of ≤ 400 mg/dL. Participants were treated with standard care, including diet, and either lovastatin immediate-release 20 mg - 40 mg daily (n= 3,304) or placebo (n= 3,301). Approximately 50% of the participants treated with lovastatin immediate-release were titrated to 40 mg daily when their LDL-C remained > 110 mg/dL at the 20-mg starting dose.
Lovastatin immediate-release reduced the risk of a first acute major coronary
event, the primary efficacy endpoint, by 37% (lovastatin immediate-release 3.5%,
placebo 5.5%; p < 0.001; Figure 3). A first acute major coronary event
was defined as myocardial infarction (54 participants on lovastatin immediate-release,
94 on placebo) or unstable angina (54 vs. 80) or sudden cardiac death (8 vs.
9). Furthermore, among the secondary endpoints, lovastatin immediate-release
reduced the risk of unstable angina by 32% (1.8% vs. 2.6%; p=0.023), of myocardial
infarction by 40% (1.7% vs. 2.9%; p=0.002), and of undergoing coronary revascularization
procedures (e.g., coronary artery bypass grafting or percutaneous transluminal
coronary angioplasty) by 33% (3.2% vs. 4.8%; p=0.001). Trends in risk reduction
associated with treatment with lovastatin immediate-release were consistent
across men and women, smokers and non-smokers, hypertensives and non-hypertensives,
and older and younger participants. Participants with ≥ 2 risk factors had
risk reductions (RR) in both acute major coronary events (RR 43%) and coronary
revascularization procedures (RR 37%). Because there were too few events among
those participants with age as their only risk factor in this study, the effect
of lovastatin immediate-release on outcomes could not be adequately assessed
in this subgroup.
Figure 3: Acute Major Coronary Events (Primary Endpoint)
In the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), the effect
of therapy with lovastatin on coronary atherosclerosis was assessed by coronary
angiography in hyperlipidemic patients. In this randomized, double-blind, controlled
clinical trial, patients were treated with conventional measures (usually diet
and 325 mg of aspirin every other day) and either lovastatin 20 mg - 80 mg daily
or placebo. Angiograms were evaluated at baseline and at two years by computerized
quantitative coronary angiography (QCA). Lovastatin significantly slowed the
progression of lesions as measured by the mean change per-patient in minimum
lumen diameter (the primary endpoint) and percent diameter stenosis, and decreased
the proportions of patients categorized with disease progression (33% vs. 50%)
and with new lesions (16% vs. 32%).
In a similarly designed trial, the Monitored Atherosclerosis Regression Study (MARS), patients were treated with diet and either lovastatin 80 mg daily or placebo. No statistically significant difference between lovastatin and placebo was seen for the primary endpoint (mean change per patient in percent diameter stenosis of all lesions), or for most secondary QCA endpoints. Visual assessment by angiographers who formed a consensus opinion of overall angiographic change (Global Change Score) was also a secondary endpoint. By this endpoint, significant slowing of disease was seen, with regression in 23% of patients treated with lovastatin compared to 11% of placebo patients.
The effect of lovastatin on the progression of atherosclerosis in the coronary arteries has been corroborated by similar findings in another vasculature. In the Asymptomatic Carotid Artery Progression Study (ACAPS), the effect of therapy with lovastatin on carotid atherosclerosis was assessed by B-mode ultrasonography in hyperlipidemic patients with early carotid lesions and without known coronary heart disease at baseline. In this double- blind, controlled clinical trial, 919 patients were randomized in a 2 x 2 factorial design to placebo, lovastatin 10-40 mg daily and/or warfarin. Ultrasonograms of the carotid walls were used to determine the change per patient from baseline to three years in mean maximum intimal-medial thickness (IMT) of 12 measured segments. There was a significant regression of carotid lesions in patients receiving lovastatin alone compared to those receiving placebo alone (p=0.001). The predictive value of changes in IMT for stroke has not yet been established. In the lovastatin group there was a significant reduction in the number of patients with major cardiovascular events relative to the placebo group (5 vs. 14) and a significant reduction in all-cause mortality (1 vs. 8).
There was a high prevalence of baseline lenticular opacities in the patient population included in the early clinical trials with lovastatin immediate-release. During these trials the appearance of new opacities was noted in both the lovastatin immediate-release and placebo groups. There was no clinically significant change in visual acuity in the patients who had new opacities reported nor was any patient, including those with opacities noted at baseline, discontinued from therapy because of a decrease in visual acuity.
A three-year, double-blind, placebo-controlled study in hypercholesterolemic
patients to assess the effect of lovastatin immediate-release on the human lens
demonstrated that there were no clinically or statistically significant differences
between the lovastatin immediate-release and placebo groups in the incidence,
type or progression of lenticular opacities. There are no controlled clinical
data assessing the lens available for treatment beyond three years.
1. Kantola, T, et al. Clin Pharmacol Ther 1998; 63(4):397-402.