Atherosclerosis 139 Suppl. 1 (1998) S15–S22

Cerivastatin in primary hyperlipidemia—a multicenter analysis ofefficacy and safety1

Evan Stein *

Medical Research Laboratories, 2 Tesseneer Dri6e, Highland Heights, KY 41076, USA

Abstract

Cerivastatin, a novel, synthetic, and enantiomerically pure 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductaseinhibitor, has been administered, in clinical trials, to over 2700 patients with primary hypercholesterolemia, of whom over 1000received treatment for periods of up to 1 year. A global, pooled analysis of the efficacy, safety, and tolerability of cerivastatin wasperformed on data obtained from all randomized, double-blind studies in which cerivastatin at doses of 0.025–0.4 mg/day werecompared with either placebo or active comparators. All studies had a 10-week, diet-controlled run-in period, the last 6 weeks ofwhich included administration of single-blind placebo. Efficacy analysis of the pooled data at 8 weeks post-randomization showedthat in comparison with placebo, cerivastatin achieved significant dose-dependent reductions in low-density lipoprotein cholesterol(LDL-C), the primary efficacy parameter, of between 14.2 and 36.1%. Reductions in LDL-C were accompanied by significantreductions in total cholesterol and triglycerides, together with increases in high-density lipoprotein cholesterol (HDL-C). Themagnitude of the reduction in plasma triglycerides was strongly related to baseline triglyceride levels. In patients with baselineplasma triglycerides of \250 mg/dl, treatment with 0.4 mg/day cerivastatin decreased these levels by 37%. Cerivastatin was welltolerated, with the type and incidence of clinical adverse effects comparable to that of placebo and comparator drugs. Theincidence of biochemical adverse effects was also similar to that seen with either placebo or comparator drugs and wasindependent of the dose of cerivastatin. Less than 1% of patients treated with cerivastatin at doses of 0.025–0.4 mg/dayexperienced clinically significant increases in either hepatic transaminases (\3× the upper limit of normal) or creatinephosphokinase (CPK) (\5× the upper limit of normal). The good tolerability of cerivastatin was reflected in a low rate ofpremature withdrawal from treatment, below or comparable to that of placebo-treatment. The pooled efficacy and safety analyseshave shown that at 1% of the doses of other statins, cerivastatin is a safe, well-tolerated, and highly effective HMG-CoA reductaseinhibitor for the treatment of type IIa and IIb hypercholesterolemia. © 1998 Published by Elsevier Science Ireland Ltd. All rightsreserved.

Keywords: Low density cholesterol; Hyperlipidemia; Clinical efficacy

1. Introduction

In patients with primary hypercholesterolemia, de-creasing elevated levels of plasma low-density lipo-protein (LDL) cholesterol is the primary target ofcholesterol-lowering therapy. Currently, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in-hibitors (statins) are considered the drugs of first choicefor the treatment of hypercholesterolemia in patients

who have failed to respond adequately to dietary ther-apy. These drugs stimulate the clearance of LDLcholesterol from the plasma via LDL receptors. Bycompetitively and reversibly inhibiting HMG-CoA re-ductase, they decrease cholesterol synthesis, which inturn leads to a compensatory increase in LDL choles-terol receptor activity and enhanced clearance ofplasma LDL cholesterol by the liver [1].

Cerivastatin, a new, synthetic, potent, and enantio-metrically pure HMG-CoA reductase inhibitor, de-creases plasma LDL cholesterol at ultra-low doses. Itscapacity to decrease LDL cholesterol is derived from itsvery high affinity for HMG-CoA reductase [2]. Cerivas-

* Tel:. +1-606-7818877; Fax: +1-606-7819310.1 Reprinted from the American Journal of Cardiology with permis-

sion.

0021-9150/98/$19.00 © 1998 Published by Elsevier Science Ireland Ltd. All rights reserved.PII: S 0 0 2 1 -9150 (98 )00189 -0

E. Stein / Atherosclerosis 139 Suppl. 1 (1998) S15–S22S16

Table 1Baseline demographics and lipid parameters (patients valid for efficacy)

Placebo (n=520)Cerivastatin (mg)

0.05 (n=590) 0.1 (n=487)0.025 (n=218) 0.2 (n=758) 0.3 (n=408) 0.4 (n=132)

62.0 62 0 58.057.0 61.0Male (%) 54.0 57.053 0 54.3 53.6Mean age (years) 55.554.0 55.8 54.476.8 77.3 77 975.0 79 3Mean weight (kg) 77.6 76.2

216.8LDL-C (mg/dl)a 208.0217.2 203.5 206.7 215.4 211.6298.8 294.1 288.4297.5 295.2Total-C (mg/dl)b 298 4 296.0

49.5 48.3 49.2HDL-C (mg/dl)c 49.952.3 54.2 51.2162.9 189.2 181.7140.2 198.3Trig (mg/dl)d 144.8 167.4

a LDL-C, low density lipoprobin cholesterol.b Total-C, tolal choleshrol.c HDL-C, high density lipoprotein cholesterol.d Trig, triglyceride.

Table 2Mean percent change in low density lipoprotein cholesterol at week 8 for selected patient subgroups (efficacy population)

PlaceboCerivastatin (mg)Patient group

0.05 0.1 0.2 0.30.025 0.4

All −15.8−14.2 −22.4 −28.2 −31.3 −36 1 0.3−14.7 −21.3 −26.8−12.6 −29.3Male −34.6 0.4−17.4 −24.2 −30.0Female −34.2−16.3 −37.6 0.1−13.2 −20.8 −26.8−7.9 −26.1540 years −32.8 −1.4

−14.0]40 yearsB65 years −15.8 −21.6 −27.8 −31.3 −35.8 0.4−17.9 −25.5 −30.1−17.8 −33.4]65 years −38.0 0.7

−14.1Type IIa lipid abnormality −15.8 −23.8 −29.4 −32.9 −36.4 0.1−15.7Type IIb lipid abnormality −20.0−14.8 −26.3 −28.7 −34.2 0.7

tatin also possesses a high affinity for liver tissue, thetarget organ for drug action. As a consequence thereis little systemic exposure to either cerivastatin or itsactive metabolites. Preclinical toxicology studies haveshown excellent tolerability of cerivastatin at doseswell in excess of those intended for clinical use [3].

Among the statins, cerivastatin is notable for itsuncomplicated pharmacokinetic profile [4,5], its lowpotential for interaction with other drugs [6–10], andits suitability for use in both young and elderly sub-jects [11], as well as those with impaired renal func-tion [12].

To date, cerivastatin has been studied in more than2700 patients with primary hypercholesterolemia, andthe results have been compared in studies involving641 patients on placebo, simvastatin, lovastatin,pravastatin, and/or gemfibrozil. The effects of cerivas-tatin have also been studied in patients with mixedhyperlipidemia and with familial hypercholesterolemia.Data from all the randomized, double-blind studieswith a placebo and/or comparator arm were includedin a global, pooled analysis of efficacy and safety, theresults of which provide the focus for this review.

2. Overview of clinical efficacy

2.1. Background

The pooled efficacy analysis included patients whoreceived at least 8 weeks of active therapy in Phase IIastudies as well as those from all the pivotal Phase IIband III clinical trials. In all these studies cerivastatinwas compared with placebo and/or comparator hy-polipidemic agents under randomized, double-blindconditions. All studies incorporated an identical designwith a 10-week diet-controlled run-in period, the last 6weeks of which included administration of single-blindplacebo. Eligible patients were then randomized toonce-daily cerivastatin at doses of either 0.025, 0.05,0.1, 0.2, 0.3 or 0.4 mg, placebo, or the comparatordrug. Efficacy analyses for the pooled data were per-formed 8 weeks post-randomization. This endpoint waschosen as the basis for evaluation because the hypolipi-demic effects of statins are fully established by 8 weeks;patient compliance with drug therapy is usually optimalover this period, and all studies could meet this time-point for lipid measurements.

E. Stein / Atherosclerosis 139 Suppl. 1 (1998) S15–S22 S17

Fig. 1. Mean percent change in low-density lipoprotein (LDL) cholesterol from baseline to endpoint (week 8) in patients valid for efficacy; n,number of subjects on each dose of cerivastatin or on placebo.

Fig. 2. Mean percent change in total cholesterol (Total-C) from baseline to endpoint (week 8) in patients valid from efficacy; n, number of subjectson each dose of cerivastatin or on placebo.

2.2. Demographics

The study population consisted of 3113 male andfemale patients with primary hypercholesterolemia, ofwhom 2593 received cerivastatin and 520 placebo. De-mographic characteristics of the study population, 60%of whom were male patients, are shown in Table 1,together with baseline lipid levels which were broadlycomparable in all patients.

2.3. Primary efficacy parameter, LDL cholesterol

The pooled efficacy analyses showed that at dosesof 0.025–0.2 mg/day (Table 2), cerivastatin producedsignificant dose-dependent reductions in LDL choles-terol of 14.2–28.2%, which increased to 31.3 and36.1% with doses of 0.3 and 0.4 mg/day, respectively(Fig. 1).

2.4. Secondary efficacy parameters

Secondary efficacy parameters were changes frombaseline in total cholesterol, triglycerides, and high-den-sity lipoprotein (HDL) cholesterol. Cerivastatin pro-duced significant dose-dependent reductions in totalcholesterol of up to 26.8% (Fig. 2), and reductions inplasma triglyceride levels of up to 36% with administra-tion of 0.4 mg/day. The reduction in triglycerides wasdependent on baseline triglycerides and greatest in pa-tients with the highest triglyceride levels at baseline. Inpatients with baseline triglycerides \250 mg/dl,cerivastatin at a dose of 0.4 mg decreased plasmatriglycerides by 36% compared with reductions of 10%in those with baseline levels of B150 mg/dl (Fig. 3).Like most other statins, cerivastatin produced modestincreases in HDL cholesterol of 4–8% which wereunrelated to the dose of drug administered (Fig. 4).

E. Stein / Atherosclerosis 139 Suppl. 1 (1998) S15–S22S18

Fig. 3. Mean percent change in triglycerides (Trig) from baseline to endpoint (week 8) in relation to baseline triglyceride levels (efficacypopulation); n, number of subjects on each dose of cerivastatin or on placebo.

Fig. 4. Mean percent change in high-density lipoprotein (HDL) cholesterol from baseline to endpoint (week 8) in patients valid for efficacy; n,number of subjects on each dose of cerivastatin or on placebo.

2.5. Subgroup e6aluation

The size of the pooled population was sufficientlylarge to enable the efficacy of cerivastatin to be analyzedin various subgroups. Thus, the effects of cerivastatin atdoses in the range 0.025–0.4 mg/day were compared inmales and females; young (B40 years), middle-aged(40–65 years), and elderly patients (\65 years); insmokers and nonsmokers; in relation to alcohol con-sumption, concomitant medications, and concomitantrisk factors for coronary artery disease; as well as inpatients with different types of lipid abnormalities (typeIIa vs type IIb hypercholesterolemia; type II defined aselevated LDL cholesterol (\160 mg/dl) with IIa havingtriglycerides B250 mg/dl and IIb \250 mg/dl).

Subgroup analyses of the pooled efficacy datashowed that of the various parameters assessed, themost marked differences in response to cerivastatinoccurred in females and older patients (Table 2). Thegreater response to cerivastatin, measured in terms ofreductions in LDL cholesterol, may however havebeen due to differences in body mass between malesand females and young and elderly subjects andtherefore related to the effects of drug dosage ratherthan to any intrinsic gender or age-related res-ponses to the drug. These findings in older subjectsmay be clinically relevant in treating these sub-groups, which form the majority of subjects treatedwith statins.

E. Stein / Atherosclerosis 139 Suppl. 1 (1998) S15–S22 S19

Table 3Median treatment duration in days (placebo-controlled studies)

Active comparatoraCerivastatin (mg) Placebo

0.05 0.1 0.2 0.30.025 0.4

421 584 882Number 372263 138 403 641Minb 7.0 2.0 1.0 1.0 1.0 4.0 2.0 1.0

88.00 108.50Median 84.0084.00 113.50 56.00 88.00 84 00196.0 201.0 203.0 198.0 78.0105.0 203.0Maxc 201.0

a Active comparators: lovastatin, simvastatin.b Min, minimum.c Max, maximum.

Table 4Mean treatment duration (days9S.D.) for patients completing 1 year of treatment

Active comparatoraCerivastatin (mg)

0.025 0.05 0.1 0.2 0.3

362.1 363.1Days of treatment 362.1372.1 346.4 363.2929.2 926.4 925.0 925.8 913.5 929.8

a Active comparators: lovastotin, simvastotin.

3. Overview of safety and tolerability

3.1. Background

The pooled safety analyses included all patients inthe cerivastatin phase II and III clinical trials who wererandomized to and received any dose of cerivastatinduring either double-blind, controlled efficacy periodsof 4–32 weeks or double-blind, placebo-controlled effi-cacy periods of 4–24 weeks. Longer-term safety wasassessed in patients who had received treatment withcerivastatin for periods of up to 1 year in the long-termextension phases to the pivotal phase IIb or phase IIItrials.

Throughout the trials, patients were routinely moni-

tored for adverse clinical and biochemical events, withparticular emphasis given to changes in serum transam-inases (alanine transaminase and aspartate transami-nase) and creatine phosphokinase levels.

3.2. Demographics

The total study population for the safety analysisconsisted of 4009 patients with primary hypercholes-terolemia, of whom 2839 received cerivastatin at dosesof 0.025–0.4 mg/day, 529 received comparator statins,and 641 received placebo. The 1-year study populationconsisted of a total of 1442 patients, of whom 1155received cerivastatin and 287 received comparatorstatins. Tables 3 and 4 show the median and meanduration of therapy in the placebo-controlled and long-term extension studies, respectively.

3.3. Ad6erse e6ents

The pooled safety analyses showed that the type andincidence of adverse events was similar in the cerivas-tatin, placebo, and active comparator groups. Of theten most frequently reported adverse events, no signifi-cant differences were evident in incidence rates betweentreatment with cerivastatin and either placebo or activecomparators (Table 5). Similarly, there was no signifi-cant difference between cerivastatin, at any dose,placebo, and active comparators in the incidence ofadverse events that were attributed to study treatment.In all treatment groups, headache and gastrointestinaldisturbances were the most common drug-related ad-verse events (Table 6). Overall adverse events were

Table 5Percent incidence rates of the ten most frequent adverse events

PlaceboActive com-Cerivoshtin (allparatorbdoses)a

6.3 8.9Flu syndrome 4.87.07.8Headache 6.5

7.76.3 7.5Pharyngitis4.7Rhinitis 5.5 5.93.1Abdominal pain 5.4 4.13.3Diarrhea 4.8 3.94.1 3.6 3.4Back pain3.5 4.1 3.3Sinusitis

2.83.6Arthralgia 3.61.1Myalgia 2.0 3.6

a Cerivastatin 0.025–0.4 mg/day.b Active comparator: lovastatin, simvastatin.

E. Stein / Atherosclerosis 139 Suppl. 1 (1998) S15–S22S20

Table 6Percent most frequent treatment-related adverse events

Cerivastatin (mg) Active com- Placebo (n=641)parator (n=

403)a

0.025 (n= 0.05 (n=421) 0.1 (n=584) 0.2 (n=882) 0.3 (n=512) 0.4 (n=138)2631)

4.5 2.9 4.2Headache 5.70.4 2.2 4.5 3.6Dyspepsia 1.5 1.7 2.7 2.4 1.2 0.7 2.5 2.2

1.5Abdominal 2.4 3.4 2.0 1.6 1.4 3.0 3.3pain

3.8 1.9 1.5Diarrhea 1.62.3 3.6 2.7 2.7Asthenia 1.5 1.9 1.5 1.5 2.9 1.4 1.6 2.0

1.7 2.2 0.7Back pain 1.20.8 1.4 0.5 1.21.7 1.4 1.5 2.51.1 1.4Flatulence 2.0 1.7

1.5Rash 1.2 2.2 0.9 0.8 0.0 3.2 1.6Nausea 1.5 1.2 1.0 1.4 1.6 0.0 3.0 1.1

0.7 0.3 1.1 0.81.5 1.4Myalgia 2.7 0.50.8Arthralgia 1.9 1.5 0.9 1.6 0.0 2.0 0.3

0.7 1.4 0.7 2.0 2.2 1.7Constipation 2.00.41.2 0.7 0.6 1.6 0.00.0 1.0Sinusitis 0.9

a Active comparator: lovastatin, simvashtin.

rarely serious and led to discontinuation of therapyduring acute administration in only 1.6% of all cerivas-tatin-treated patients compared with 3.2% of patientsreceiving active comparators and 2.2% of patients onplacebo. Discontinuation rates during long-term ther-apy were 1.9–4.7% in the cerivastatin treatment groupscompared with 3.1% for comparator agents.

3.4. Hepatic enzymes

Treatment with HMG-CoA reductase inhibitors hasbeen associated with occasional and usually transientincreases in serum transaminase levels. The pooledsafety analysis showed that there were no significantdifferences between cerivastatin, active comparators ofcerivastatin, and placebo with respect to clinically sig-nificant increases in levels of either alanine transami-nase or aspartate transaminase. Importantly, there wasno evidence of any dose-related increases in transami-nase levels with cerivastatin up to the maximum dosetested, 0.4 mg/day (Table 7).

3.5. Muscle enzymes

In all treatment groups, elevations in creatine phos-phokinase of 5–10× the upper limit of normal oc-curred with an incidence of B1% and there was noassociation with muscle pain. There was also no evi-dence to indicate that clinically significant increases inlevels of creatine phosphokinase were related to increas-ing doses of cerivastatin (Table 7). Creatine phosphoki-nase values \10× the upper limit of normal were notnoted at the highest doses of cerivastatin tested and

were scattered equally throughout the lower doses ofcerivastatin, placebo, and comparator groups. Therewere no cases of clinical myositis.

4. Discussion and conclusions

Cerivastatin, a new third-generation HMG-CoA re-ductase inhibitor, has been administered to more than2700 patients worldwide in a series of phase II and IIIclinical studies designed to evaluate its efficacy, safety,and tolerability in the treatment of primary hyperc-holesterolemia. As the results of the pooled efficacy andsafety analyses have clearly demonstrated, cerivastatinis an efficacious, safe, and well-tolerated statin and apotentially important addition to the armamentariumof hypolipidemic agents for the treatment ofhypercholesterolemia.

Compared with placebo-treated patients, cerivastatinat doses in the range 0.1–0.4 mg/day produced signifi-cant dose-dependent reductions in LDL cholesterol.The decrease of \28% achieved with 0.2 mg/daycerivastatin are in the range of LDL cholesterol reduc-tion produced by 40 mg/day pravastatin in the recentWest of Scotland Coronary Prevention Study (WO-SCOPS) [13], and the Cholesterol and Recurrent Events(CARE) trial [14], and the reductions of \36% with0.4 mg/day cerivastatin are comparable to those seenwith 20–40 mg/day simvastatin in the ScandinavianSimvastatin Survival Study (4S) [15]. These landmarkprimary and secondary coronary prevention trials, re-spectively, have demonstrated for the first time thattreatment with these two statins not only significantlydecreases the risk of coronary events and death due to

E. Stein / Atherosclerosis 139 Suppl. 1 (1998) S15–S22 S21

Table 7Percent incidence rates of biochemical adverse effects

Cerivastatin (mg) Active com-Biochemical Placebo (n=641)parartor (n=parameter

529)a

0.05 (n=421) 0.1 (n=584)0.025 (n=263) 0.2 (n=882) 0.3 (n=512) 0.4 (n=138)

ALTb

– 0.78 0.58 0.26 1.56 – 1.30\2 to 53× 0.53ULNe

– 0.26 0.19 –\3 to 55× 0.22 – 0.22 0.18ULN\5×ULN n 0.26 0.19 0.13 0.22 – – 0.18

ASTc

0.39 0.49 0.36 – 0.61\2 to 53× – 0.79 0.33ULN\3 to 55× – – – 0.24 0.41 – – 0.16

ULN–\5×ULN 0.18n 0.12 – – – 0.16

CPKd

0.47 – – 0.55 – 0.88 0.47 0 39\5 to 510×ULN

0.29 – 0.28\10×ULN –0.47 – 0.23 0 39

a Active comparator: lavastatin, simvostatin.b ALT, alanine transaminase.c AST, aspartate transaminase.d CPK, creatine phosphokinase.e ULN, upper limit of normal.

coronary artery disease but also decreases the risk ofall-cause mortality. The reductions in LDL cholesterolachievable with cerivastatin suggest that at microgramdoses cerivastatin should be both clinically and thera-peutically beneficial.

In common with currently available statins, cerivas-tatin shows a log-linear dose-response, producing anincremental 6% reduction in LDL cholesterol each timethe dose was doubled. Studies on lovastatin [16],pravastatin [17], fluvastatin [18], and simvastatin [19]suggest that doses of 80, 40, 80 and 80 mg, respectively,are close to the dose-ceiling for these agents, with dosesabove these levels either not having been explored orhaving been found to be associated with unacceptableside effects. The present pooled analyses on cerivastatinindicate that the log-linear dose-response may extendbeyond doses of 0.4 mg. Indeed, a recent Phase IIastudy has shown that doubling the dose of cerivastatinto 0.8 mg/day produced reductions in LDL cholesterolof 44%, consistent with a continued log-linear dose-re-sponse, and comparable to the reductions achieved withhigher doses of the most effective statins [20]. Althoughof only 4 weeks duration, this dose was not associatedwith any incremental increases in clinical or laboratoryabnormalities.

Similar to other statins [21], cerivastatin not onlysignificantly decreased levels of LDL cholesterol butalso had a beneficial effect on the entire lipid profile of

hypercholesterolemic patients. Significant dose-depen-dent reductions occurred in total cholesterol andtriglycerides together with modest increases in HDLcholesterol. As recently reported for other statins[22,23] reduction in triglyceride levels observed withcerivastatin was more pronounced, the higher the base-line plasma triglyceride level, indicating that cerivas-tatin is suitable for treatment of both type IIa and IIbor combined hyperlipidemia.

Based on the pooled safety analysis, cerivastatin hasan exceptionally good safety profile, with an incidenceof adverse effects comparable to that of placebo. Incontrast to existing statins, there was no evidence ofany dose-related increase in adverse effects with cerivas-tatin [24]. Unique among the statin class, cerivastatinproduces its lipid-lowering effects at microgram ratherthan milligram doses. This ultra-low dosage regimen isthought to contribute to its good safety profile.

Hepatotoxicity and myotoxicity are the most seriousadverse effects associated with HMG-CoA reductaseinhibitors, with the frequency of significant abnormali-ties in hepatic transaminases usually related to the doseof drug [24]. Creatine phosphokinase abnormalities andmyocytis may be more related to statin catabolism, asagents dependent solely on metabolism by the microso-mal cytochrome P-450 3A4 enzyme pathway may bemore likely to result in toxicity [25]. The uniquecatabolism of cerivastatin by the hepatic cytochrome

E. Stein / Atherosclerosis 139 Suppl. 1 (1998) S15–S22S22

system indicates far less likelihood for such toxicity[9,10]. Clinically significant increases in either aspartatetransaminase/alanine transaminase or creatine phos-phokinase were rare after treatment with cerivastatinand, unlike most other statins, were unrelated to drugdosage.

Premature discontinuation of therapy usually pro-vides a useful measure of overall drug tolerability. Ingeneral, HMG-CoA reductase inhibitors are well-toler-ated agents, with only 1–4.6% of patients discontinuingtherapy because of adverse events [24]. Rates of with-drawal in the present study were similarly low forpatients receiving cerivastatin.

In conclusion, this pooled analysis of the efficacy andsafety of cerivastatin has shown that at doses of up to0.4 mg/day, cerivastatin is an effective, safe, and well-tolerated agent for the treatment of type IIa and IIbprimary hypercholesterolemia. The absence of anydose-related increases in either clinical or laboratoryabnormalities suggests that at currently approved dosescerivastatin is highly effective and that the doses maybe safely increased to provide potentially greater lipidlowering effects without compromising safety.

References

[1] Blum CB, Levy RI. Current therapy for hypercholesterolemia. JAm Med Assoc 1989;261:3582–7.

[2] Angerbauer R, Bischoff H, Steinke W, Ritter W. BAY w 6228:hypolipidemic HMG-CoA reductase inhibitor. Drugs Fut1994;19:537–41.

[3] Bischoff H, Angerbauer R, Bender J, Bischoff E, Faggiotto A,Petzinna D, et al. Cerivastatin: pharmacology of a novel syn-thetic and high active HMG-CoA reductase inhibitor.Atherosclerosis 1997;135:119–30.

[4] Frey R, Mazzu AL, Ritter W, Heller AH, Kuhlmann J. Safetyand tolerability of rivastatin, a novel HMG-CoA reductaseinhibitor, in phase-I single dose studies, (Abstract). NaunynSchmiedebergs Arch Pharmacol 1993;347:30.

[5] Mazzu AL, Lettieri J, Kaiser L, Frey R, Heller AH. Ascendingmultiple dose safety, tolerability and pharmacodynamics of ri-vastatin in humans, (Abstract no. PIII-95). Clin Pharmacol Ther1993;53:230.

[6] Muck W, Ritter W, Dietrich H, Frey R, Kuhlmann J. Influenceof the antacid Maalox and the H2-antagonist cimetidine on thepharmacokinetics of cerivastatin. Int J Clin Pharmacol Ther1997;35:621–4.

[7] Muck W, Ritter W, Frey R, Wetzelsberger N, Lucker PW,Kulhmann J. Influence of cholestyramine on the pharmacokinet-ics of cerivastatin. Int J Clin Pharmacol Ther 1997;35:250–4.

[8] Lettieri J, Krol G, Mazzu AL, Fiebach M, Heller AH. Lack ofpharmacokinetic interaction between cerivastatin, a new HMG-CoA reductase inhibitor, and digoxin. Atherosclerosis1997;130:S29–A109.

[9] Schall R, Muller FO, Hundt HKL, Ritter W, Duursema L,Groenewoud G, et al. No pharmacokinetic or pharmacodynamic

interaction between rivastatin and warfarin. J Clin Pharmacol1995;35:306–13.

[10] Muck W, Ochmann K, Unger S, Kuhlmann J. Influence oferythromycin pre-and co-treatment on single-dose pharmacoki-netics of the HMG-CoA reductase inhibitor cerivastatin. ClinPharmacol Ther 1998;53:469–73.

[11] Lettieri J, Krol G, Mazzu AL, Shah A, Falk R, Beck C. Effectof age and gender on the steady-state pharmacokinetics ofrivastatin, (Abstract no. PPDM 8159). Pharm Res 1993;10:S338.

[12] Vormfelde S, Freudenthaler S, Muck W, Heyen P, Schmage N,Kuhlmann J, et al. Pharmacokinetics of cerivastatin in subjectswith normal and impaired renal function. Br J Clin Pharmacol1997; in press.

[13] Shepherd J, Cobbe SM, Ford CG, Isles AR, Lorimer PW,MacFarlane JH, et al. Prevention of coronary heart disease withpravastatin in men with hypercholesterolemia. New Engl J Med1995;333:1301–7.

[14] Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD,Cole TG, et al., for the Cholesterol and Recurrent Events TrialInvestigator set. The effect of pravastatin on coronary eventsafter myocardial infarction in patients with average cholesterollevels. New Engl J Med 1996;335:1001–1009.

[15] Pedersen TR and the Scandinavian Simvastatin Survival StudyGroup. Randomized trial of cholesterol lowering in 4444 pa-tients with coronary heart disease: the Scandinavian SimvastatinSurvival Study (4S). Lancet 1994;344:1383–1389.

[16] Bradford RH, Shear CL, Chremos AN, Dujovne C, DowntonM, Franklin FA, et al. Expanded Clinical Evaluation of Lovas-tatin (EXCEL) study results. I. Efficacy in modifying plasmalipoproteins and adverse event profile in 8245 patients withmoderate hypercholesterolaemia. Arch Intern Med 1991;151:43–9.

[17] Peters TK, Mehra M, Muratti EN. Efficacy and safety offluvastatin in hypertensive patients. An analysis of a clinical trialdatabase. Am J Hypertens 1993;6:340S–5S.

[18] Hunninghake DB, Mellies MJ, Goldberg AC, Kuo PT, KostisJB, Schrott HG, et al. Efficacy and safety of pravastatin inpatients with primary hypercholesterolemia. I. A dose-responsestudy. Atherosclerosis 1990;85:81–94.

[19] McDowell IFW, Smye M, Trinick T, Shortt JA, Archibald MP,Trimble ER, et al. Simvastatin in severe hypercholesterolaemia: aplacebo-controlled trial. Br J Clin Pharmacol 1991;31:340–3.

[20] Stein EA, Isaacsohn J, Stoltz R, Mazzu AL, Liu MC, Lane C, etal. Efficacy and safety of 0.8 mg dosage of cerivastatin, a novelHMG-CoA reductase inhibitor, (Abstract). J Am Coll Cardiol1998;31:281A.

[21] Hsu I, Spinler SA, Johnson NE. Comparative evaluation of thesafety and efficacy of HMG-CoA reductase inhibitor monother-apy in the treatment of primary hypercholesterolemia. AnnPharmacother 1995;29:743–59.

[22] Bakker-Arkema RG. Efficacy and safety of a new HMG-CoAreductase inhibitor atorvastatin, in patients with hypertriglyce-ridemia. J Am Med Assoc 1996;275:128–33.

[23] Stein EA, Lane M, Laskarzewski PL. Comparison of statins inhypertriglyceridemia. Am J Cardiol 1998;81:66B–9B.

[24] Blum CB. Comparison of properties of four inhibitors of 3-hy-droxy-3-methylglutaryl coenzyme A reductase. Am J Cardiol1994;73:3D–11D.

[25] Transon C, Leemann T, Dayer P. In vitro comparative inhibi-tion profiles of major human drug metabolising cytochromeP450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors. Eur J Clin Pharmacol 1996;50:209–15.

.