"The U.S. Food and Drug Administration today approved Kynamro (mipomersen sodium) injection as an addition to lipid-lowering medications and diet to treat patients with a rare type of high cholesterol called homozygous familial hypercholesterolemi"...
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 this range.
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 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. The independent effect of raising HDL or lowering TG on the Altoprev® Lovastatin Im ia e-re e e 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 immediate-release formulation.
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)
|Drug||Cmax (ng/mL)||Cmin (ng/mL)||T ma(h)||AUC0-24hr (ng• hr/mL)|
|Altoprev® 40 mg*||5.5||5.8||17.3||13.4||2.6||3.1||9.1||4.3||14.2||11.8||77||87||263||171|
|Lovastatin IR 40 mg**||7.8||11.9||36.2||26.6||0.4||0.7||2.4||2.1||3.3||5.3||45||83||252||186|
|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 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
hypercholesterolemic 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 Tmax and lower Cmax 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 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 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 study1, 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 betahydroxyacid 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 βhydroxyacid metabolite (measured using a chemical assay – liquid chromatography/tandem mass spectrometry) of 1.94-fold and 1.57fold, 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 Coadministered Drug or Grapefruit Juice||Dosing of Lovastatin||AUC Ratio* (with / without coadministered drug) No Effect = 1.00||Cmax Ratio* (with / without coadministered drug) No Effect = 1.00|
|Lovastatin†||Lovastatin acid†||Lovastatin †||Lovastatin acid†|
|Contraindicated with lovastatin, [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]|
|Itraconazole‡||200 mg QD for 4 days||40 mg on Day 4||§||20||> 25§||13.0|
|100 mg QD for 4 days||40 mg on Day 4||> 14.8§||15.4||14.5||11.5|
|Avoid with lovastatin, [see WARNINGS AND PRECAUTIONS]|
|Cyclosporine||Not describedβ||10 mg QD for 10 days on Day 10||3-to 5-fold||NRa||NRa||NRa|
|Gemfibrozil||600 mg BID for 3 days||40 mg on Day 3||0.96||2.80||0.88||2.81|
|Grapefruit Juice¶ (high dose)||200 mL of doublestrength TID for 2 days||80 mg on Day 3||15.3||5.0||11.8||4.0|
|Grapefruit Juice¶ (low dose)||8 oz (about 250 mL) of single-strengthÞ for 4 days||40 mg on Day 3||1.94||1.57||2.26||1.65|
|Avoid taking with > 20 mg lovastatin, [see WARNINGS AND PRECAUTIONS]|
|Diltiazem||120 mg BID for 14 days||20 mg on Day 14||3.57e||NDΠ||4.33e||NDΠ|
|No dosing adjustments required for the following:|
|Propanolol||40 mg BID for 2.5 days||20 mg on Day 2||NDΠ||0.87||NDΠ||0.81|
|* Results based on a chemical
†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.
Þ Single-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.
ß Cyclosporine-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.
ΠAnalyte 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 with chlorpropamide.
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.
Last reviewed on RxList: 5/23/2014
This monograph has been modified to include the generic and brand name in many instances.
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