A multiple-dose pharmacodynamic, safety, and pharmacokinetic comparison of extended- and immediate-release formulations of lovastatin.
BACKGROUND
Because lovastatin is efficiently extracted by the liver and because its administration in divided doses is associated with increased efficacy, an extended-release (ER) formulation may have the potential for a dose-sparing advantage relative to the immediate-release (IR) formulation in the treatment of hypercholesterolemia.


OBJECTIVE
This study compared the short-term pharmacodynamics, safety, and pharmacokinetics of multiple doses of lovastatin ER with those of lovastatin IR in patients with fasting low-density lipoprotein cholesterol (LDL-C) levels between 130 and 250 mg/dL and fasting triglyceride levels < 350 mg/dL.


METHODS
The study had a randomized, single-blind, positive-controlled, 2-way crossover design, with a 4-week diet/placebo run-in period and two 4-week active-treatment periods. During period 1, patients received either lovastatin ER or lovastatin IR (both 40 mg OD). After 4 weeks of the initial study treatment and a 2-week washout period, patients were switched to the alternate treatment (period 2). Pharmacodynamic parameters (LDL-C, high-density lipoprotein cholesterol, total cholesterol, and triglyceride levels) were evaluated by combining data from weeks 3 and 4 of treatment. In a pharmacokinetic substudy, maximum plasma concentrations (C(max)) and area under the plasma concentration-time curve from zero to 24 hours (AUC(024)) were determined for lovastatin, lovastatin acid, and total and active inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase on days 1 and 28 of active treatment. The geometric mean ratio of AUC(0-24) (lovastatin ER/lovastatin IR) was also calculated for each of these substances.


RESULTS
Of 76 patients who entered the run-in period, 26 (12 men, 14 women; mean age, 56.2 years) were randomized to receive active treatment and 24 were included in the efficacy analysis; 13 patients were included in the pharmacokinetic substudy, 12 of whom had complete pharmacokinetic data. Compared with lovastatin IR, lovastatin ER produced a 3.9% greater reduction in LDL-C (P = 0.044). Changes in other lipid parameters were not statistically significant. In the pharmacokinetic substudy, C(max) values for lovastatin, lovastatin acid, and in hibitors of HMG-CoA reductase were lower at day 28 with lovastatin ER than with lovastatin IR. The AUC(0-24) ratio for lovastatin was 1.91 (90% CI, 1.77 - 3.35), reflecting higher bioavailability of the prodrug with lovastatin ER; in contrast, the ratios for lovastatin acid and active and total inhibitors of HMG-CoA reductase were < 1.


CONCLUSIONS
In this short-term study in a small number of patients, lovastatin ER 40 mg produced significantly greater LDL-C lowering than did an equal dose of lovastatin IR, with a relatively low C(max) and comparable systemic exposure to lovastatin acid and active and total inhibitors of HMG-CoA reductase. Lovastatin ER was well tolerated, with no discontinuations due to adverse events.
Davidson
Michael H
MH
Chicago Center for Clinical Research, Illinois 60610, USA. mdavidson@protocare.com
Lukacsko
Peter
P
Sun
Jim X
JX
Phillips
Gale
G
Walters
Edward
E
Sterman
Arnold
A
Niecestro
Robert
R
Friedhoff
Lawrence
L
D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D002784:Cholesterol / Q000097:blood; D003692:Delayed-Action Preparations; D005260:Female; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy*; D008111:Liver Function Tests; D008148:Lovastatin / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010349:Patient Compliance; D016037:Single-Blind Method
D000924:Anticholesteremic Agents; D003692:Delayed-Action Preparations; D002784:Cholesterol; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases