The Effect of Dosing Time on Efficacy and Safety of an Extended-Release Formulation of Lovastatin in Patients with Primary Hypercholesterolemia*

 

Michael H. Davidson, MD, FACC^a

Peter Lukacsko, PhD^b

Jim X. Sun, PhD^b

Gale Phillips, BA^b

Ed Walter, MS^b

Arnold Sterman, MD, MBA^b

Lawrence Friedhoff, MD, PhD^b

 

^aChicago Center for Clinical Research, Chicago, IL

^bAndrx Laboratories, Inc; Division of Andrx Corporation, Fort Lauderdale, FL

 

*This study was supported by grant from Andrx Group Inc., Fort Lauderdale, FL.

 

KEY WORDS: lovastatin, extended release, dosing time, efficacy

 

Abstract

Background: An extended-release formulation of lovastatin (lovastatin ER) was developed to minimize systemic concentrations of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors and enhance inhibitor efficacy.

Methods: The effects of dosing time on efficacy and safety of lovastatin ER in patients with primary hypercholesterolemia were evaluated in a multicenter, randomized, parallel-group study with a 4-week diet/placebo run-in period, followed by a 4-week active-treatment period. Patients (n = 68) were randomized to receive lovastatin ER 40-mg before breakfast, after dinner, or before bedtime. The primary efficacy variable was the percentage change in low-density lipoprotein cholesterol (LDL-C) levels from baseline to endpoint. Secondary efficacy variables included percent changes from baseline to endpoint in high-density lipoprotein cholesterol (HDL-C), total cholesterol, and triglyceride levels. Safety was evaluated by assessing adverse events, clinical laboratory values, changes in physical examinations, and vital signs.

Results: Although lovastatin ER administered before bedtime produced a numerically greater reduction in LDL-C (-36.9%) compared with before breakfast (-32.0%) or after dinner (-34.1%), this was not statistically significant. The percentage changes between treatment groups in HDL-C (range, 7.4% to 11.1%), total cholesterol (range, -22.2% to -25.5%), and triglycerides (range, -10.2% to -19.7%) were also numerically greater before bedtime but not statistically significant. No serious adverse events occurred and there were no clinically meaningful changes in safety parameters.

Conclusions: Lovastatin ER is effective in lowering LDL-C, total cholesterol, and triglyceride levels and increasing HDL-C level when administered before breakfast, after dinner, or before bedtime.

 

INTRODUCTION

An extended-release formulation of lovastatin (lovastatin ER) was developed to minimize systemic concentrations of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors and enhance inhibitor efficacy.¹ Lovastatin, a lactone prodrug, readily hydrolyzes to its active form, b-hydroxyacid, as a specific and competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.² Inhibition of HMG-CoA reductase by lovastatin suppresses cholesterol synthesis and subsequently leads to upregulated production of hepatic low-density lipoprotein receptors. Commercially available as an immediate-release tablet (lovastatin IR), lovastatin is generally well tolerated and produces a dose-related decrease in low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglyceride levels when administered at 20 to 80 mg daily.^3,4

The pharmacokinetics of lovastatin are well known. Efficient hepatic extraction and significant first-pass metabolism of lovastatin result in <5% of the drug reaching the systemic circulation as the active inhibitor of HMG-CoA reductase.² After oral administration, approximately 83% of the drug is excreted in the feces and only 10% in the urine.⁵ When the lovastatin IR formulation is given immediately after a meal, bioavailability of lovastatin is 50% greater than when given under fasting conditions.⁵

In a large clinical study, it was observed that lovastatin IR (20 mg twice daily) produced significantly greater reductions in the LDL-C level of patients with hypercholesterolemia than did a 40-mg, once-daily dosage of lovastatin IR, suggesting that more sustained delivery of drug would result in greater efficacy.³ Recently, an extended-release formulation of lovastatin ER, offering a more sustained delivery of the drug, was developed (Andrx Laboratories Inc., Division of Andrx Inc., Fort Lauderdale, FL). In pharmacokinetic studies, lovastatin ER demonstrated delayed-delivery and extended-release properties by achieving a lower peak plasma concentration (C_max) and a prolonged time to C_max for lovastatin and active metabolites, compared with lovastatin IR.^1,6 Because of the enhanced bioavailability of lovastatin IR when taken with food^5,7 and the slightly enhanced efficacy of evening dosing observed with statins,⁸ this study evaluated the efficacy and safety of lovastatin ER given in the morning after an overnight fast, after the evening meal, and before bedtime.

 

MethodS

Study Design

This was a multicenter, randomized, parallel-group study in patients with primary hypercholesterolemia. A 4-week diet/placebo run-in period preceded randomization to active treatment. Patients not currently following at least a National Cholesterol Education Program (NCEP) step 1 diet were given detailed instructions on day 1 (start of the 4-week diet/placebo run-in period) and received periodic reinforcement during the study. After the 4‑week run-in period, patients were randomized to 4 weeks of active treatment in one of the following treatment groups: (1) lovastatin ER 40-mg tablet 1 hour before breakfast following an overnight fast; (2) lovastatin ER 40-mg tablet immediately after dinner; or (3) lovastatin ER 40‑mg tablet before bedtime (at approximately 10:00 pm).

            The study protocol and informed consent were approved by each institution's Ethical Review Board prior to conducting the study. All participating patients provided written informed consent prior to enrollment.

 

Study Population

Following an initial screening visit, patients were eligible to start the 4-week diet/placebo run-in period if they met the following criteria: (1) 21 to 70 years of age; (2) completion of 6-week washout of any lipid-modifying agent (including over-the-counter products) prior to randomization; (3) fasting plasma triglyceride level <350 mg/dL; and (4) creatine phosphokinase (CPK) value <250 mU/mL at screening. All enrolled patients met US NCEP II guidelines.

            Important exclusion criteria included the following: (1) premenopausal women who were not surgically sterile; (2) intolerance to HMG-CoA reductase inhibitors; (3) clinically significant hepatic, renal, gastrointestinal, metabolic, neurologic, pulmonary, endocrine, or psychiatric disorders; (4) history within the past 5 years or current diagnosis of malignancy; (5) acute myocardial infarction, coronary revascularization procedure, acute coronary insufficiency, or uncontrolled systemic hypertension within the past 2 years; (6) a current diagnosis of secondary hypercholesterolemia or diabetes mellitus; (7) concomitant medications that might interact with lovastatin; (8) history of underlying hepatic disease; or (9) serum creatinine >1.5 mg/dL at screening.

 

Lipid Assessments

Patients had laboratory assessments at screening, 1 week before randomization, at start of treatment, and after week 3 and week 4 of active treatment. After a 12-hour fast, blood samples were taken for lipid determinations, including HDL‑C, total cholesterol, and triglycerides. LDL-C levels were calculated using the Friedewald formula.⁹ The primary efficacy variable was the percentage change in LDL-C levels from baseline to endpoint. Percentage changes in the levels of HDL-C, total cholesterol, and triglycerides from baseline to endpoint were secondary efficacy variables. Baseline was defined as the average of the last 2 values before starting active treatment, while the endpoint was defined as the last value after starting active treatment. Additionally, the number and percentage of patients achieving the NCEP II LDL-C goal at endpoint were summarized according to treatment group and risk group.

 

Safety and Tolerability

Assessment of safety and tolerability was based on the incidence and frequency of adverse events as well as changes in clinical laboratory values, physical examinations, and vital signs. Laboratory tests, including serum aminotransferases, CPK, and serum chemistry, were analyzed by Medical Research Laboratories, Highland Heights, Kentucky.

 

Statistical Analysis

Summary statistics were determined according to treatment group for baseline values and percentage changes from baseline after 3 and 4 weeks of active treatment for all efficacy variables. A two-way analysis of variance, with treatment group and center as factors, was used to analyze the percentage change from baseline to endpoint in all efficacy variables. Least-squares means for these values with corresponding standard errors and 95% confidence intervals were tabulated for each treatment group. All treatment group comparisons were performed. For each comparison, the least-squares mean for difference in percentage change with corresponding standard error and P value for testing difference equal to zero were tabulated. All tests were two-sided, and P values <.05 were considered statistically significant.

 

RESULTS

Patient Disposition

A total of 76 patients were enrolled in the study. During the diet/placebo run-in period, 8 patients withdrew from the study (1, agitation/trouble sleeping; 2, withdrawal of consent; and 5, noncompliance). Therefore, a total of 68 patients were randomized into the active-treatment period. Patients were randomized to one of the following lovastatin ER treatment groups: (1) before breakfast (n = 22); (2) after dinner (n = 23); and (3) before bedtime (n = 23). All patients who were randomized to treatment completed the study.

 

Demographics and Baseline Characteristics

The 68 randomized patients included 37 (54.4%) men and 31 (45.6%) women. Of these, 64 (94.1%) were white and 4 (5.9%) were African-American. Table 1 summarizes baseline demographic and clinical characteristics of the randomized patient population by treatment group. Each treatment group had similar values for mean age and height, whereas the value for mean weight ranged from 76.0 to 83.3 kg among the 3 groups. In addition, there was some variability between treatment arms in the number of patients in each risk group.

 

Lipid Parameters

All 68 randomized patients with at least 1 subsequent lipid determination were included in the efficacy analysis. The mean medication compliance rate was >98%. Table 2 summarizes the percentage change in LDL-C levels from baseline to endpoint for each treatment group. There was variability among the 3 treatment groups in mean baseline LDL-C levels. The greatest least-squares mean percentage change in LDL-C level from baseline to endpoint occurred in the group receiving lovastatin ER before bedtime (36.9% reduction). The groups receiving lovastatin ER before breakfast and after dinner experienced mean reductions in LDL-C level of 32.0% and 34.1%, respectively. There were no statistically significant differences between treatment groups in mean percentage reduction in LDL-C levels. Overall, 59 (86.8%) patients achieved their NCEP II LDL-C goal level for their risk group at endpoint.

            The mean baseline HDL-C levels were similar among the 3 groups. The greatest least-squares mean percentage increase in HDL-C level from baseline to endpoint occurred in the group receiving lovastatin ER before bedtime (11.1%). Differences in mean percentage change in HDL were not statistically significant between treatment groups (Table 2).

            There was some variability in mean baseline total cholesterol and triglyceride levels among the 3 groups. The greatest least-squares mean percentage reduction in total cholesterol and triglyceride levels from baseline to endpoint occurred in the group receiving lovastatin ER before bedtime, with reductions of 25.5% and 19.7%, respectively (Table 2). There were no statistically significant differences between treatment groups in mean percentage reductions in total cholesterol or triglyceride levels from baseline to endpoint.

 

Safety and Tolerability

There were no serious adverse events or deaths reported during the study. One patient discontinued during the diet/placebo run-in period due to agitation and trouble sleeping. Overall, 9 (40.9%) of the patients in the before-breakfast group, 6 (26.1%) in the after-dinner group, and 9 (39.1%) in the before-bedtime group experienced at least 1 adverse event. The body system with the greatest number of patients experiencing at least 1 adverse event was "body as a whole," with infection being the most commonly reported event (incidence ranging from 4.3% to 4.5% among the treatment groups). The majority of adverse events were mild to moderate, with the exception of 1 case of severe stomatitis considered unrelated to study drug. Five patients had adverse events that were suspected to be drug related (before breakfast, 4 [18.2%]; after dinner, 0 [0%]; before bedtime, 1 [4.3%]). Among the body systems, more drug-related adverse events were reported for the digestive system, with 1 case of constipation in the before-breakfast group and 1 case of nausea in the before-bedtime group. All drug-related adverse events were considered to be mild to moderate in intensity, and there were no discontinuations due to study drug.

            No clinically significant changes in physical examinations, vitals signs, or chemistry laboratory parameters were reported during the study. All patients had AST values £2 times the upper limit of normal throughout the study. With 1 exception, patients had ALT values £2 times the upper limit of normal. A single patient in the after-dinner treatment group had a single isolated ALT value between 2 and 3 times the upper limit of normal. No CPK elevations >5 times the upper limit of normal occurred, and the majority of patients maintained CPK within normal limits.

 

Discussion

Daily administration of lovastatin ER 40 mg resulted in least-squares mean percentage reductions in LDL-C levels from baseline to endpoint of 32.0%, 34.1%, and 36.9% when taken before breakfast, after dinner, or before bedtime, respectively. The relatively greater LDL-C reduction observed when lovastatin ER was administered before bedtime is consistent with the physiologic finding that most intracellular cholesterol synthesis occurs during the night. Lovastatin ER allows for sustained and continuous delivery of active drug to the target organ (the liver), and bedtime dosing may allow for inhibition of cholesterol synthesis at the optimal time in the circadial course of cholesterol metabolism. Administration before bedtime also resulted in a greater least-squares mean percentage increase in HDL-C level (11.1%) from baseline to endpoint compared with the changes observed with administration at the other time points. Similarly, least-squares mean change in total cholesterol level observed in the group receiving lovastatin before bedtime (25.5% reduction) was numerically greater compared with the other time points. The least-squares mean reduction in triglyceride level observed in the group receiving lovastatin before bedtime (19.7%) was almost twice that seen in the other treatment groups (before breakfast, 10.2%; after dinner, 11.2%). Based on the observed greater changes in lipids, it is recommended that lovastatin ER be dosed before bedtime. Despite the observed numeric differences between treatment groups, the mean percentage changes in lipid parameters were not statistically significant.

            There were some demographic differences in the treatment groups as well as some differences in baseline lipid levels. None of these variations, however, would explain the observed differences in lipid changes among the 3 treatment groups. It has been well established that the percentage change in triglyceride levels is greater when baseline triglyceride levels are higher.¹⁰ In this study, the group receiving lovastatin ER after dinner had the highest baseline triglyceride level, yet the group receiving lovastatin ER before bedtime experienced a greater triglyceride lowering. The after-dinner group also had the highest baseline LDL-C and total cholesterol levels; but again, greatest lowering of these parameters was observed with the before-bedtime group.

            In the Expanded Clinical Evaluation of Lovastatin (EXCEL) study, treatment with divided doses of lovastatin IR 40 mg (20 mg twice daily) was associated with a 34% mean reduction in LDL-C level compared with 30% with 40 mg dosed once daily.^3,11 In the current report, the 36.9% mean reduction in LDL-C level observed in the group receiving lovastatin ER 40 mg before bedtime approximates but is greater than the results of treatment with lovastatin IR 20 mg twice daily in the EXCEL study.^3,11 Once daily dosing is preferable in terms of patient adherence to therapy. The extent of LDL-C lowering demonstrated with lovastatin ER in the current study is consistent with that in other studies using 40 mg of the extended-release formulation.^6,12 Thus, lovastatin ER 40 mg appears to be more efficacious than lovastatin IR 40 mg. Additionally, results of this study demonstrate that lovastatin ER was well tolerated and safe. These collective results suggest that the risk-benefit ratio of lovastatin ER 40 mg is at least equivalent to lovastatin IR 40 mg/day. LowThe lower C_max of active inhibitors of HMG-CoA reductase associated with lovastatin ER suggest a safety advantage since inhibitor activity may correlate with risk of myopathy with statins.^1,12,13 However, the current investigation was not designed or powered to test this hypothesis. Further studies are needed to support this finding.

 

CONCLUSION

Lovastatin ER was effective in lowering LDL-C, total cholesterol, and triglyceride levels as well as increasing the HDL-C level, regardless of the time of dosing (ie, before breakfast, after dinner, or before bedtime). Although there was no statistical difference in the extent of LDL-C lowering between the different times of drug administration, there was a numerically greater reduction in LDL-C when lovastatin ER was administered before bedtime.

 

REFERENCES

1.     Sun JX, Phillips G, Shen J, et al: Comparative pharmacokinetics of lovastatin extended-release tablets and lovastatin immediate-release tablets in humans. [submitted to: J Clin Pharmacol 2001.]

2.     Moghadasian MH: Clinical pharmacology of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Life Sci 65:1329-1337, 1999.

3.     Bradford RH, Shear CL, Chremos AN, et al: Expanded Clinical Evaluation of Lovastatin (EXCEL) study results, I: Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. Arch Intern Med 151:43-49, 1991.

4.     Lovastatin Study Groups I Through IV. Lovastatin 5-year safety and efficacy study. Arch Intern Med 153:1079-1087, 1993.

5.     Mevacor [package insert]. Whitehouse Station, NJ, Merck & Co, Inc, 2000.

6.     Davidson MH, Lukacsko P, Friedhoff L, Sterman A: A multiple-dose safety, pharmacokinetic, and pharmacodynamic study comparing an extended-release formulation of lovastatin with the immediate-release formulation. [submitted to: Am J Cardiol 2001.]

7.     Dobrinska MR, Stubbs RJ, Gregg MH, et al: Effects of dose and food on HMG-CoA reductase inhibitor profiles after lovastatin (Mevacor) [abstract]. Pharm Res 5(S-182):1334, 1988.

8.     Mück W, Frey R, Unger S, Voith B: Pharmacokinetics of cerivastatin when administered under fasted and fed conditions in the morning or evening. Int J Clin Pharmacol Ther 38:298-303, 2000.

9.     Friedewald WT, Levy RI, Fredrickson DS: Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499-502, 1972.

10.   Roberts WC: The rule of 5 and the rule of 7 in lipid-lowering by statin drugs [editorial]. Am J Cardiol 80:106-107, 1997.

11.   Bradford RH, Shear CL, Chremos AN, et al: Expanded Clinical Evaluation of Lovastatin (EXCEL) study results: two-year efficacy and safety follow-up. Am J Cardiol 74:667-673, 1994.

12.   Crouse JR, Lukacsko P, Niecestro R, and the Lovastatin Extended-Release Study Group: Dose response, safety, and efficacy of an extended-release formulation of lovastatin in adults with hypercholesterolemia. [submitted to: Am J Cardiol 2001.]

13.   Gruer PJ, Vega JM, Mercuri MF, et al: Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin. Am J Cardiol 84:811-815, 1999.

Table 1. Demographic and Baseline Characteristics of Randomized Patients

Characteristics	Before Breakfast (n = 22)	After Dinner (n = 23)	Before Bedtime (n = 23)
Age Men/women (%) Weight (kg) Height (cm) Mean plasma lipids, mg/dL LDL-C Total cholesterol HDL-C Triglycerides Risk groups, n (%) <2 Risk factors for HD ³2 Risk factors for HD With CHD, PVD, or CVD	56.6 (9.7) 63.6 (36.4) 82.6 (13.1) 172.7 (8.4)   171.8 255.0 49.7 167.9         12 (54.5)         8 (36.4)        2 (9.1)	57.1 (9.1) 43.5 (56.5) 76.0 (12.9) 167.6 (8.6)   185.0 272.7 49.1 195.3        11 (47.8)      12 (52.2)   -	58.5 (9.4) 56.5 (43.5) 83.3 (14.3) 171.2 (11.2)   169.7 252.8 46.8 181.8           6 (26.1)       14 (60.9)         3 (13.0)
All values are expressed as mean (standard deviation) unless stated otherwise. Mean plasma lipid levels are expressed as the raw mean values at baseline. LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol; HD = heart disease; CHD = coronary heart disease; PVD = peripheral vascular disease; CVD = cerebrovascular disease.

 

Table 2. Least-Squares Mean Percentage Change (SE) in Lipid Parameters from Baseline to Endpoint

 

	Lovastatin ER			P Value*
	Before Breakfast (n = 22)	After Dinner (n = 23)	Before Bedtime (n = 23)
LDL-C	-32.0 (2.55)	-34.1 (2.48)	-36.9 (2.49)	.3809
HDL-C	8.4 (2.30)	7.4 (2.24)	11.1 (2.24)	.4863
Triglyceride	-10.2 (5.08)	-11.2 (4.95)	-19.7 (4.96)	.4815
Total cholesterol	-22.2 (2.01)	-23.6 (1.95)	-25.5 (1.96)	.3337

n = number of patients with values at both baseline and endpoint; SE = standard error.

*P value is derived from a two-way analysis of variance for percentage change with treatment group and center as factors.