SUN ET AL LOVASTATIN EXTENDED- AND IMMEDIATE-RELEASE TABLETS PHARMACOKINETICS AND PHARMACODYNAMICS Comparative Pharmacokinetics of Lovastatin Extended-Release Tablets and Lovastatin Immediate-Release Tablets in Humans Jim X. Sun, PhD, Robert Niecestro, PhD, Gale Phillips, BA, Jason Shen, MS, Peter Lukacsko, PhD, and Lawrence Friedhoff, MD, PhD L ovastatin, a lactone prodrug that hydrolyzes to the corresponding β-hydroxyacid (lovastatin acid), is a specific and competitive inhibitor of 3-hydroxy-3- methylglutaryl-coenzyme A (HMG-CoA) reductase. 1,2 Animal and clinical data have shown that this com- pound can suppress cholesterol synthesis and regulate the number of hepatic low-density lipoprotein (LDL) receptors. 3-5 An immediate-release (IR) tablet of lovastatin (Mevacor ® ) for oral administration has been commercially available for more than 10 years. The standard starting dose for lovastatin IR tablets is 20 mg once daily with the evening meal and can be increased to the maximum dose of 80 mg either in single or di- vided doses. 6 Bradford et al 7 reported that lovastatin IR given as 20 mg twice daily produced a significantly greater reduc- tion in LDL cholesterol levels in patients than when given as 40 mg once daily. Subsequently, McClelland et al 8 have shown in dogs that systemic concentrations of HMG-CoA reductase inhibitors could be minimized and inhibitor efficacy could be enhanced by oral ad- ministration of the trimethammonium salt of the β-hydroxyacid of simvastatin through an extended- release dosage form. In addition, Duggan et al 9 and Vickers et al 10 reported that lovastatin and simvastatin were more efficiently extracted by the liver—the target organ for both compounds—than their corresponding β-hydroxyacids, with subsequent minimization of sys- temic burden. These findings suggest that compared with a conventional dosage form, an extended-release dosage form of lovastatin may provide a dose-sparing advantage and improved safety profile. Based on the results described above, an extended- release dosage form of lovastatin (lovastatin extended- release [ER] tablets) was developed by Andrx Pharma- 198 • J Clin Pharmacol 2002;42:198-204 The pharmacokinetics of lovastatin and its active metabolite lovastatin acid was evaluated in 9 healthy subjects in a three-period crossover study following a single oral dose of lovastatin extended-release (ER) tablets and lovastatin im- mediate-release (IR) tablets. Participants were dosed with lovastatin IR 40 mg tablets following a standard breakfast, lovastatin ER 40 mg tablets following a standard breakfast, and lovastatin ER 40 mg tablets under fasting conditions. Se- rial plasma samples were collected for up to 48 hours postdose and assayed for lovastatin and lovastatin acid using a liquid chromatography/mass spectroscopy/mass spectros- copy method. Lovastatin ER tablets, unlike lovastatin IR tab- lets, exhibited delayed- and extended-release characteristics. The relative bioavailability, in terms of area under the curve values, of lovastatin (156%) and lovastatin acid (124%) was greater from lovastatin ER tablets as compared with lovastatin IR tablets when given with breakfast. An even greater increase in the bioavailability of lovastatin (261%) and lovastatin acid (231%) was observed when the lovastatin ER tablets were administered under fasting conditions. Thus, greater gastrointestinal tract drug absorption of lovastatin from lovastatin ER tablets was demonstrated. Ingestion of a standard breakfast prior to administration of lovastatin ER tablets decreased absorption of lovastatin by approximately 40%, relative to lovastatin ER tablets under fasting conditions. Journal of Clinical Pharmacology, 2002;42:198-204 ©2002 the American College of Clinical Pharmacology From the Department of Clinical Research, Andrx Laboratories, Inc., Andrx Corporation, Fort Lauderdale, Florida. This study was supported by a grant from Andrx Group, Inc., Fort Lauderdale, Florida. Submitted for publica- tion May 13, 2001; revised version accepted September 6, 2001. Address for reprints: Robert Niecestro, Andrx Laboratories, Inc., 401 Hackensack Avenue, Hackensack, NJ 02601.