Inhibition of HMG-CoA reductase by lovastatin accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol. Sustained inhibition of cholesterol synthesis in the liver also decreases levels of very-low-density lipoproteins. The maximum LDL-C reduction of lovastatin is usually achieved by 4 weeks and is maintained after that.
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 subjects with hypercholesterolemia at steady state, after 28 days of treatment of Altoprev 40 mg, is summarized in Table 4.
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.
At the 40 mg dose, 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).
Altoprev appears to have dose linearity for doses from 10 mg up to 60 mg per day.
Effect of Food
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 5.
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.
Lovastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, an 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.
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.
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 (not an approved dose of Altoprev) [see Dosage and Administration (2.2)], 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 (8.5)].
Male and Female Patients
In a single dose pharmacokinetic study with Altoprev, there were no statistically significant differences in pharmacokinetic parameters between males (n=12) and females (n=10), although exposure tended to be higher in males than females.
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.
Drug Interaction Studies
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 (5.1) and Drug Interactions (7)].
Lovastatin is a substrate for CYP3A4 [see Drug Interactions (7)]. 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.
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.