Mechanism Of Action
Lovastatin is a lactone that is readily hydrolyzed in
vivo to the corresponding β-hydroxyacid, a strong 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.
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.
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
Lovastatin immediate-release tablets have been shown to
reduce elevated LDL-C concentrations. LDL is formed from very low-density
lipoprotein (VLDL) and is catabolized predominantly by the highaffinity 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. 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.
The appearance of lovastatin in plasma from an Altoprev®
extended-release tablet is slower and more prolonged compared to the lovastatin
A pharmacokinetic study carried out with Altoprev®
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 Altoprev® 40 mg to
lovastatin immediate-release 40 mg, are summarized in Table 3.
Table 3 : Altoprev® vs . Lovastatin Immediate-Release
(IR) (Steady-State Pharmacokinetic Parameters at Day 28)
||AUC0-24hr (ng• hr/mL)
|Altoprev® 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, AUC0-24h = 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 Altoprev® 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 hypercholes terolemic patients
(n=12) after 28 days of administration of Altoprev® or lovastatin immediate-release
The extended-release properties of Altoprev® are
characterized by a prolonged absorptive phase, which results in a longer T and
lower C for lovastatin (pro-drug) 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 Altoprev® 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 Altoprev® compared to that of a single dose measured using a
chemical assay. Altoprev® appears to have dose linearity for doses from 10 mg
up to 60 mg per day.
When Altoprev® was given after a meal, plasma
concentrations of lovastatin and lovastatin acid were about 0.5 - 0.6 times
those found when Altoprev® was administered in the fasting state, indicating
that food decreases the bioavailability of Altoprev® . There was an association
between the bioavailability of Altoprev® 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 Altoprev® 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 Altoprev® was
administered at bedtime. Results of this study are displayed in Table 4.
Table 4 : Altoprev® 40 mg (Least Squares Mean Percent
Changes from Baseline to Endpoint at 4 Weeks of Treatment*)
|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 Altoprev®, was 190% compared to
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.
Distribution: 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
Metabolism: Metabolism studies with Altoprev® have
not been conducted.
Lovastatin is a lactone that is readily hydrolyzed in
vivo to the corresponding β-hydroxyacid, a strong 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. Strong inhibitors of CYP3A can raise
the plasma levels of HMG-CoA reductase inhibitory activity and increase the
risk of myopathy [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].
Lovastatin is a substrate for CYP3A4 [see DRUG
INTERACTIONS]. Grapefruit juice contains one or more components that
inhibit CYP3A and can increase the plasma concentrations of drugs metabolized
by CYP3A4. In one study , 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.
Table 5 : The Effect of Other Drugs on Lovastatin
Exposure When Both Were Co-administered
|Coadministered Drug or Grapefruit Juice
||Dosing of Co-administered Drug orGrapefruit Juice
||Dosing of Lovastatin
||AUC Ratio *(with / without co-administered drug) No Effect = 1.00
||Cmax Ratio*(with / without co-administered drug) No Effect = 1.00
|Contraindicated with lovastatin, [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]
||200 mg QD for 4 days
||40 mg on Day 4
|| > 25§
|100 mg QD for 4 days
||40 mg on Day 4
|| > 14.8§
|Avoid with lovastatin, [see WARNINGS AND PRECAUTIONS]
||10 mg QD for 10 days on Day 10
||600 mg BID for 3 days
||40 mg on Day 3
|Grapefruit Juice¶ (high dose)
||200 mL of double-strength TID for 2 days
||80 mg on Day 3
|Grapefruit Juice¶ (low dose)
||8 oz (about 250 mL)of single-strengthÞ for 4 days
||40 mg on Day 3
|Avoid taking with > 20 mg lovastatin, [see WARNINGS AND PRECAUTIONS]
||120 mg bid ior 14 days
||on4 a 0D 2
|No dosing adjustments required for the following:
||40 mg BID for 2.5 days
||20 mg on Day 2
|* Results based on a chemical assay.
† Lovastatin acid refers to the β-hydroxyacid of lovastatin.
‡ Results could be representative of strong CYP3A inhibitors such as
ketoconazole, posaconazole, clarithromycin, telithromycin, HIV protease
inhibitors, and nefazodone.
§The mean total AUC of lovastatin without itraconazole phase could not be
determined due to assay's detection limit.
¶The effect of amounts of grapefruit juice between those used in these two
studies on lovastatin 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 lovastatin and 30 and 90 minutes following single dose lovastatin
on Day 3.
ÞSingle-strength: one can of frozen concentrate diluted with 3 cans of water.
Grapefruit juice was administered with breakfast for 3 days, and lovastatin was
administered in the evening on Day 3.
βCyclosporine-treated post kidney
transplant patients with stable graft function, transplanted at least 9 months
prior to study.
aNR = Analyte not reported.
eLactone converted to acid by hydrolysis prior to analysis. Figure represents
total unmetabolized acid and lactone.
||Analyte not determined
Digoxin: In patients with hypercholesterolemia,
concomitant administration of lovastatin and digoxin resulted in no effect on
digoxin plasma concentrations.
Oral Hypoglycemic Agents : In pharmacokinetic
studies of lovastatin immediate-release in hypercholesterolemic non-insulin
dependent diabetic patients, there was no drug interaction with glipizide or
Excretion: In a single-dose study with Altoprev® ,
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 Altoprev® 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.
Geriatric: Lovastatin Immediate-Release
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 Use in Specific Populations].
Pediatric: Pharmacokinetic data in the pediatric
population are not available.
Gender: In a single dose pharmacokinetic study
with Altoprev® , 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 Altoprev® , there was no
clinically significant difference in LDL-C reduction between men and women.
Renal Impairment: In a study of patients with
severe renal impairment (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.
Hemodialysis : The effect of hemodialysis on
plasma levels of lovastatin and its metabolites have not been studied.
Hepatic Impairment: No pharmacokinetic studies
with Altoprev® have been conducted in patients with hepatic impairment.
Altoprev® 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 Altoprev® 10 to
60 mg in the evening was compared to placebo. Altoprev® produced dose related reductions
in LDL-C and Total-C. Altoprev® produced mean reductions in TG across all doses
that varied from approximately 10% to 25%. Altoprev® produced mean increases in
HDL-C across all doses that varied from approximately 9% to 13%.
The lipid changes with Altoprev® treatment in this study,
from baseline to endpoint, are displayed in Table 6.
Table 6 : Altoprev® vs. Placebo (Mean Percent Change
from Baseline After 12 Weeks )*
|Altoprev® 10 mg
|Altoprev® 20 mg
|Altoprev® 40 mg
|Altoprev® 60 mg
|N = the number of patients with values at both baseline
* Except for the HDL-C elevation with Altoprev® 10 mg, all lipid changes with Altoprev®
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):
Figure 2 : Altoprev® 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
Expanded Clinical Evaluation Of Lovastatin (EXCEL) Study
Lovastatin immediate-release was compared to placebo in
8,245 patients with hypercholesterolemia [Total-C 240-300mg/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
7) observed in lovastatin immediate-release-treated patients were dose-related
and significantly different from placebo (p ≤ 0.001). These results were
sustained throughout the study.
Table 7 : Lovastatin Immediate-Release (IR) vs . Placebo
(Percent Change from Baseline - Average Values Between Weeks 12 and 48)
||LDL-C/ HDL-C (mean)
||TOTAL-C/ HDL-C (mean)
|Lovastatin IR 20mg q.p.m.
|40 mg q.p.m.
|20 mg b.i.d.
|40 mg b.i.d.
|** Patients enrolled
Altoprev® Long-Term Study
A total of 365 patients were enrolled in an extension
study in which all patients were administered Altoprev® 40 mg or 60 mg once
daily for up to 6 months of treatment. The lipid-altering effects of Altoprev®
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 Altoprev®, 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.
Heterozygous Familial Hypercholesterolemia
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 immediaterelease 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.
Prevention Of Coronary Heart Disease
The Air Force/Texas Coronary Atherosclerosis Prevention
Study (AFCAPS/TexCAPS), a doubleblind, 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
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
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%
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
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
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