Pharmacodynamics, Safety, Tolerability,and Pharmacokinetics of the 0.8-mgDose of Cerivastatin in Patients With

Primary HypercholesterolemiaEvan Stein, MD, PhD, Jonathan Isaacsohn, MD, Randall Stoltz, PhD, Arthur Mazzu, PhD,

Ming-Chung Liu, PhD, Cindy Lane, MS, and Allen H. Heller, MD

Cerivastatin is a third generation hydroxy-methyl-glu-taryl-Co-enzyme A (HMG-CoA) reductase inhibitorproven to lower low-density lipoprotein (LDL) cholesterol28% to 31% in patients with primary hypercholesterol-emia when given at 0.3 mg/day. This study evaluatesthe safety, tolerability, pharmacodynamics, and phar-macokinetics of cerivastatin 0.8 mg once daily for 4weeks. In this randomized, double-blind, placebo-con-trolled parallel group trial conducted at 2 study centers,41 patients (63% women) with primary hypercholester-olemia were placed on an American Heart AssociationStep 1 diet for 4 weeks. Single-blind placebo was ad-ministered for the final 2 weeks, before randomization.Patients received cerivastatin 0.8 mg (n 5 28) or pla-cebo (n 5 13) once each evening for 28 days. Cerivas-tatin at 0.8 mg daily was well tolerated. No discontinu-ations occurred during the study. Adverse events weremild and transient. One cerivastatin-treated patient ex-perienced asymptomatic creatinine kinase, 83 the up-per limit of normal (ULN) elevation on the last day of the

study, which resolved 6 days after the completion of thestudy. Cerivastatin 0.8 mg daily significantly reducedLDL cholesterol compared with placebo (244.0 6 2.0%vs 2.2 6 2.8%, p <0.0001); total cholesterol (230.8 61.4% vs 2.6 6 2.1%, p <0.0001), triglycerides(211.2 6 5.9% vs 15.9 6 8.6%, p <0.02), but did notsignificantly alter high-density lipoprotein (HDL) choles-terol (3.2 6 2.1% vs 21.2 6 3.1%, p 5 NS). Thepharmacokinetics of the 0.8-mg dose revealed doseproportional elevations in the 24-hour area under thecurve and maximum plasma concentration relative to0.3- and 0.4-mg doses with no change in time to max-imum concentration or the elimination half-life inplasma. The increased efficacy and lack of clinicallysignificant laboratory abnormalities or adverse eventsdemonstrates a need for a large long-term study toconfirm the safety and efficacy of this dose of cerivas-tatin. Q1999 by Excerpta Medica, Inc.

(Am J Cardiol 1999;83:1433–1436)

Cerivastatin is a synthetic pure enantiomeric (thirdgeneration) hydroxy-methyl-glutaryl-Co-enzyme

A (HMG-CoA) reductase inhibitor that has been dem-onstrated to be safe, well-tolerated, and efficacious.The 0.3-mg daily dosage of cerivastatin reduces low-density lipoprotein (LDL) cholesterol on average up to31%.1 Cerivastatin has demonstrated an excellentsafety profile in several clinical trials, with the inci-dence of adverse effects comparable to placebo.1 Thepharmacokinetics of cerivastatin are unchanged withfood,2 and are unaltered by nifedipine,3, omeprazole,4

cimetidine,5 aluminum and magnesium hydroxide ant-acids,6 digoxin,7 or warfarin.8 Analysis of the dose-response relation of cerivastatin reveals that like otherstatins, the efficacy of LDL cholesterol lowering is loglinear, with an approximate 6% lowering of LDLcholesterol occurring with each doubling of the doseup to 0.4 mg daily.1 This study evaluates the pharma-

codynamics and short-term safety of cerivastatin 0.8mg daily compared with a placebo over a 28-day studyperiod.

METHODSStudy design and treatment regimens: This was a

double-blind, randomized, parallel group trial con-ducted at 2 study sites in the United States. Patientsreviewed and signed informed consent at the initiationof the diet run-in period. At the time of the first visit(week24), patients received a complete medical his-tory (including demographics), a complete physicalexam, ophthalmic evaluation, a 12-lead electrocardio-gram, clinical laboratory tests including safety labsand plasma lipid profile, and chest x-ray. Eligiblepatients were instructed on an American Heart Asso-ciation step 1 diet and how to complete a 3-day fooddiary. Patients received single-blind placebo for 2weeks before randomization, and those who werecompliant with the diet at week 0 were considered foreligibility in the double-blind portion of the study.

To enter the double-blind active treatment phase,mean plasma LDL cholesterol value at the 2 visitsbefore randomization (weeks22 and21) had to be$160 mg/dl or$130 mg/dl in the presence of clini-cally documented coronary artery disease, or subjects(men or postmenopausal women) had to have$2cardiovascular risk factors (systemic hypertension,

From the Metabolic and Atherosclerosis Research Center, Cincinnati,Ohio; GFI Pharmaceutical Services, Inc., Evansville, Indiana; and TheBayer Corporation, Pharmaceutical Division, West Haven, Connecti-cut. This study was supported by a research grant from Bayer Corpo-ration Pharmaceutical Division, West Haven, Connecticut. Manuscriptreceived August 20, 1998; revised manuscript received and ac-cepted January 6, 1999.

Address for reprints: Evan Stein, MD, PhD, Metabolic and Athero-sclerosis Research Center, 2350 Auburn Avenue, Cincinnati, Ohio45219.E-mail: ESTEINMRL@AOL.COM.

1433©1999 by Excerpta Medica, Inc. 0002-9149/99/$–see front matterAll rights reserved. PII S0002-9149(99)00120-4

current cigarette smoking, family history of prematurecoronary artery disease, or low high-density lipopro-tien cholesterol). Second, the patient’s plasma LDLcholesterol at the 2 eligibility visits could not bedifferent from the mean plasma LDL cholesterol forthese 2 visits by.12%. Third, the patient’s plasmatriglyceride level had to be#400 mg/dl. Patients wererandomized to receive cerivastatin 0.8 mg or placeboat a 2:1 ratio. Study drugs were administered with theevening meal between 5 and 7P.M. for 4 weeks.

Patient selection: Adults, including postmenopausalwomen, with or without hormone replacement ther-apy, aged 18 to 75 years with primary hypercholes-terolemia, as defined above, were eligible for thisstudy. Patients were excluded if they had clinicallyactive cardiovascular disease or uncontrolled hyper-tension within 3 months of entry; coronary arterybypass graft or percutaneous transluminal coronaryangioplasty 6 months before entry; hypertension withalterations in diuretic orb-blocker therapy within 2months of entry; uncontrolled diabetes mellitus orother endocrine abnormalities; unstable ophthalmicabnormalities (cataracts, or corrected visual acuity,20/50); malignancy; psychosis; active liver disease,or unexplained persistent elevations of hepatictransaminases (.1.13 upper limit of normal [ULN]),serum creatinine$2 mg/dl,$1.53 ULN, serum amy-lase.1.23 ULN; fasting serum glucose.140 mg/dl;weight .130% of ideal body weight; history of hy-persensitivity to HMG-CoA reductase inhibitors; ne-phrotic syndrome; or gastrointestinal disorders. Disal-lowed concurrent medications included aspirin, corti-costeroids, erythromycin, rifampin, androgens,immunosuppressants, or antidiabetic medications. Pa-tients were excluded if they were concomitantlytreated with other hypolipidemic medication, had usedprobucol within the prior 6 months, or had a history ofalcohol or substance abuse. Pregnant, lactating womenor women of child-bearing potential, and night shiftworkers were also excluded.

Safety assessments: During the run-in and the dou-ble-blind phases of the study, patients were seen atweekly intervals. Procedures performed during thestudy included complete medical examinations (in-cluding electrocardiogram) and ophthalmic examina-tions. Laboratory testing, including platelet aggregom-etry, and clinical assessments were performed weeklyduring the double-blind period. Complete laboratorysafety analysis, including blood chemistry, bloodcount with platelets and differential, urinalysis, andthyroid stimulating hormone were performed atscreening, twice before randomization, and thenweekly. Two days after the last dose of double-blindmedication and completion of the 48-hour pharmaco-kinetic samples, patients had an end-of-study com-plete physical examination, and an ophthalmic exam-ination.

Pharmacodynamic analysis: Plasma lipid parame-ters (total cholesterol, calculated LDL cholesterol,HDL cholesterol, and triglycerides) were obtained atscreening, and 3 times before randomization. Plasmalipids were then measured at weekly intervals. The

primary efficacy variable in this study was the percentchange from baseline in plasma LDL cholesterol atday 28. The percent changes of other lipid variables,including total cholesterol, triglycerides, and HDLcholesterol were secondary efficacy variables. Base-line measurements for all lipid parameters were ob-tained on the day of randomization. All blood andurine laboratory samples were analyzed by MedicalResearch Laboratories (Highland Heights, Kentucky),which is National Heart Lung and Blood Institute—Center for Disease Control Part III standardized.9

Pharmacokinetic methodology: Plasma levels ofcerivastatin and its major metabolites were measuredin samples drawn on day 28 at predose, and then at 1,1.5, 2, 3, 4, 6, 8, 12, 16, 20, and 24 hours postdose.Plasma levels of cerivastatin and its 2 major metabo-lites (M1 and M23) were measured by high perfor-mance liquid chromatography following extraction aspreviously described.10,11 These methods are highlyselective and ultra-sensitive; the detection limit was0.05 mg/L and 0.1 mg/L, for cerivastatin and bothmetabolites, respectively.

Statistical analysis: The number of patients random-ized for this study was not determined on statisticalgrounds, but was considered appropriate for an assess-ment of the short-term safety of the 0.8-mg dose ofcerivastatin at this stage of clinical development.Based on an n5 36 with a 2:1 active:placebo ratio,this study had the power of 90% to detect a 15%difference between cerivastatin and placebo treatmentusing a 2-sideda level of 0.025. Differences betweentreatment groups were determined using the analysisof variance with terms for center and treatment group.The interaction model was also run to determine con-sistency of analysis of variance results.

RESULTSDemographic analysis of patient population: Of the

50 patients screened and enrolled in the 4-week dietrun-in phase of the study, 41 patients met the entrycriteria and were randomized to 0.8-mg cerivastatin orplacebo. All 41 patients completed the double-blindtreatment. Analysis revealed that both treatmentgroups were well matched for demographics and base-line plasma lipid levels (Table I).

Safety analysis: ADVERSE EVENTS: No significantchanges were detected on physical examination or

TABLE I Patient Demographics

Cerivastatin(n 5 28)

Placebo(n 5 13)

Mean age (yrs*) 54.5 6 11.5 51.0 6 13.7Mean height (cm)* 167.0 6 9.0 169.1 6 7.5Mean weight (kg)* 79.2 6 11.1 77.7 6 11.2Caucasian (%) 28 (100%) 11 (85%)Men 10 (36%) 5 (39%)LDL cholesterol (mg/dl)* 174 6 28 176 6 28Total cholesterol (mg/dl)* 260 6 28 258 6 33HDL-Cholesterol (mg/dl)* 47 6 9 47 6 12Triglycerides (mg/dl)* 209 6 96 180 6 73

*Mean 6 SD.

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electrocardiogram. One patient in the cerivastatingroup developed symptoms and signs consistent withpelvic inflammatory disease on day 26; however, thispatient completed the 28-day treatment regimen. Nosignificant changes were observed in ophthalmic ex-aminations.

One adverse event was reported by 18 of 28 pa-tients (64%) given 0.8 mg of cerivastatin and by 7 of13 patients (54%) given placebo. All of the eventswere classified as mild or moderate in intensity and allbut 3 events were resolved by the end of the study.The adverse events that continued to the end of thestudy included heel pain, arthritis (hands), and anaccidental injury (toe fracture) (Table II).

LABORATORY INDEXES: Elevations in hepatictransaminase levels to.23 ULN were not observedin any patients. Two patients treated with cerivastatinhad creatinine kinase values.33 ULN, 1 of whomhad a creatinine kinase elevation 83 ULN detected atthe last study visit, but the patient was totally asymp-tomatic, and the creatinine kinase decreased rapidly tonearly normal 6 days after the termination of thestudy.

Finally, no clinically relevant changes were ob-served in other laboratory tests, including prothrombintime and partial thromboplastin time, or platelet ag-gregability.

Pharmacodynamic analysis: After 28 days of treat-ment (Figure 1), LDL cholesterol was reduced by44.0 6 2.0% (mean6 SD) on cerivastatin 0.8 mgcompared with an increase of 1.26 2.8% (p,0.0001)on placebo. Cerivastatin also reduced total cholesterol

30.8 6 1.4% versus an increase of 2.16 2.1% (p,0.0001). Triglyceride reductions of 11.26 5.9%occurred with cerivastatin, whereas those on placebohad an increase in triglycerides of 15.96 8.8% (p,0.02). HDL cholesterol increased on cerivastatinand decreased on placebo (3.26 2.1% vs21.2 63.1%); this difference was not statistically significant.

Analysis of the time course of the LDL cholesterolreduction in cerivastatin-treated patients revealed arapid effect with about 70% of the maximum effectseen after 7 days of starting treatment (Figure 2). Amaximum effect was seen by day 21 and LDL cho-lesterol remained stable at this reduced level throughday 28.

Pharmacokinetic analyses: The principal pharmaco-kinetic parameters of cerivastatin 0.8 mg are summa-rized in Table III. These data are compared with thepharmacokinetics of cerivastatin dosed at 0.3 and 0.4mg each evening in a recently completed long-termclinical trial (Bayer Study Number D96-008, data onfile). These results demonstrate that the dose-depen-dent parameters, plasma maximum concentration, and24-hour area under the curve increase in proportion todose, whereas the dose-independent parameters, max-

TABLE II Number (percent) of Patients Reporting AdverseEvents (of any cause during the study)*

Event Cerivastatin (n 5 28) Placebo (n 5 13)

Any event 18 (64%) 7 (54%)Headache 10 (36%) 2 (15%)Pharyngitis 3 (11%) 0 (0%)Back pain 2 (7%) 1 (8%)Arthralgia 2 (7%) 1 (8%)Rash 2 (7%) 0 (0%)

*If n .1.p 5 NS.

FIGURE 1. Influence of cerivastatin on plasma lipid parameters at28-day end point. C 5 cholesterol.

FIGURE 2. Influence of cerivastatin 0.8 mg on lipid parameters:time course (percentage of baseline levels). (A) LDL cholesterol.(B) Total cholesterol. *p <0.01 cerivastatin versus placebo.

TABLE III Pharmacokinetic Analysis of Cerivastatin and itsMajor Metabolites

Parameter

Cerivastatin 0.8 mg Compared WithCerivastatin 0.3 and 0.4 mg

0.3 mg(n 5 11)*

0.4 mg(n 5 16)*

0.8 mg(n 5 27)

AUC0–24 (mg*h/L) 29.3 35.9 69.9Cmax (mg/L) 5.4 6.3 13.8tmax (h) 2.0 1.9 1.5t1/2 (h) 4.2 4.0 4.2

Parameter

Cerivastatin Metabolites M1 and M23[mean (%CV)]

Metabolite M-1 Metabolite M-23

AUC0–24 (mg*h/L) 5.5 (48%) 17.0 (54%)Cmax (mg/L) 0.6 (50%) 1.4 (47%)tmax (h) 3.4 (53%) 4.5 (35%)t1/2 (h) 3.6 (40%) 5.0 (39%)

*Data from Bayer clinical study #D96-008 (unpublished data).AUC0–24: 24 hour area under the curve; Cmax: maximum plasma concen-

tration; tmax: time to maximum blood concentration; t1/2: elimination half-life.

PREVENTIVE CARDIOLOGY/PHARMACODYNAMICS AND SAFTEY OF CERIVASTATIN 1435

imum time to peak concentration, and drug elimina-tion half-life in plasma remained unchanged over thisdose range. Additionally, plasma levels of the 2 majorcerivastatin metabolites M1 and M23 were measuredand the pharmacokinetics are presented in Table III.Cerivastatin metabolites, M1 and M23, have beenshown to be approximately 50% and 100% as activeas the parent compound. Analysis revealed that.75%of the major circulating plasma components followingdosing with cerivastatin is the parent compound (Fig-ure 3).

DISCUSSIONIn this randomized, placebo-controlled, double-

blind study, treatment with cerivastatin at 0.8 mg oncedaily for 28 days was well tolerated, and although ofvery short duration and in a limited number of sub-jects, the drug was not associated with any clinicallysignificant or sustained clinical or laboratory adverseexperience. Mild to moderate transient adverse eventswere nearly equally distributed between the treatmentgroups. No subject discontinued the study drug duringthis study. Larger and longer studies are needed tofully assess the clinical and laboratory safety of thisdose.

The pharmacokinetics of the 0.8-mg dose whencompared with lower doses revealed a continued in-crease in 24-hour area under the curve and maximumconcentration proportional to the dose, whereas asexpected the time to maximum concentration andelimination half-life remained unaltered. This, cou-pled with the observations that the plasma levels ofcerivastatin metabolites contribute only about 25% tothe total plasma pool and were eliminated at the samerate as the parent compound, indicate that accumula-tion at the 0.8-mg dose is highly unlikely as it is atlower doses in patients with normal or mildly im-paired renal function.

The 0.8-mg dose of cerivastatin had a mean reduc-tion of LDL cholesterol of 44%, with concomitantreductions in total cholesterol (31%) and triglycerides(11%). The lipid-lowering effects of cerivastatin wererapid and maximum reductions were apparent after 3weeks, and were maintained for the duration of thestudy (Figure 2).

Patients with either established coronary artery dis-ease or those meeting the recently revised AmericanDiabetes Association guidelines for type 2 diabetes12

require greater LDL cholesterol reduction to achievethe National Cholesterol Education Program andAmerican Diabetic Associations treatment goal of#100 mg/dl. For example, patients with diet-treatedLDL cholesterol levels.155 mg/dl need a minimumof 36% reduction and, even median decreases of thismagnitude will fail to achieve the National Choles-terol Education Program goal in 50% of these sub-jects. In this small study of 28 subjects treated withcerivastatin 0.8 mg, 79% had an LDL cholesterolreduction.35%, and 43% of patients achieved LDLcholesterol reductions of.45%. Only$20 mg ator-vastatin, and$40 mg simvastatin, or$80 mg lova-statin doses, and now, cerivastatin 0.8 mg have shownmean reductions in LDL cholesterol.40%.

Acknowledgment: The authors thank Kenneth B.Pomerantz, PhD, for his assistance with preparation ofthis manuscript.

1. Insull W, Stein E, Whalen E, Ripa S, and the Cerivastatin Study Group.Cerivastatin: a new potent HMG-CoA reductase inhibitor: efficacy and tolerabil-ity in primary hypercholesterolemia.J Am Coll Cardiol1997;29:46A.2. Mazzu A, Lettieri J, Heller AH. Pharmacokinetics of cerivastatin administra-tion with and without food in the morning and evening.Atherosclerosis1997;139(suppl):S29.3. Sachse R, Brendel E, Muck W, Rohde G, Ochmann K, Horstmann R. Nodrug-drug interaction between cerivastatin and nifedipine.Arch Pharmacol1998;357:R174.4. Muck W, Ochmann K, Rohde G, Unger S, Kuhlmann J. No drug-druginteractions between cerivastatin and omeprazole.Arch Pharmacol1998;357:R175.5. Frey R, Ritter W, Unger S, Ochmann K, Wingenzer W. Phase I study toinvestigate the effects of cimetidine on the pharmacokinetics of cerivastatin—anew HMG-CoA reductase inhibitor.Atherosclerosis1997;130:S27.6. Muck W, Ritter W, Dietrich H, Frey R, Kuhlmann J. Influence of the antiacidMaaloxt and the H2-antagonist cimetidine on the pharmacokinetics of cerivas-tatin. Int J Clin Pharmacol Ther1997;35:261–264.7. Lettieri JT, Krol GJ, Mazzu A, Fiebach MZ, Heller AH. Lack of pharmaco-kinetic interaction between cerivastatin, a new HMG-CoA reductase inhibitor,and digoxin.Atherosclerosis1997;130:S29.8. Schall R, Muller FO, Hundt HK, Ritter W, Duursema L, Groenewoud G. Nopharmacokinetic or pharmacodynamic interaction between rivastatin and warfa-rin. J Clin Pharmacol1995;35:306–313.9. Myers GL, Cooper GR, Winn CL, Smith SJ. The Centers for Disease Control-National Heart, Lung and Blood Institute Lipid Standardization Program: anapproach to accurate and precise lipid measurements.Clin Lab Med1989;9:105–135.10. Krol GJ, Beck GW, Ritter W, Lettieri JT. LC separation and inducedfluorometric detection of rivastatin in blood plasma.J Pharm Biomed Anal1993;11:1269–1275.11. Krol GJ, Beck GW, Ritter W, Lettieri JT, Ness GC, Lopez D. Determinationof rivastatin levels in plasma samples by HPLC and enzyme inhibition assays. In:Reid R, Wilson ID, eds. Biofluid and Tissue Analysis for Drugs, IncludingHypolipidaemics. 23 vol. Cambridge: Royal Society of Chemistry 1994:147–156.12. Management of dyslipidemia in adults with diabetes. American DiabetesAssociation. Diabetes Care 1998;21:179–182.

FIGURE 3. Plasma concentration-time profile of cerivastatin andthe major metabolites M1 and M23 following the 0.8-mg dose.Means were calculated when at least two-thirds of the data wereabove the limit of quantitation (LOQ). In calculation of mean val-ues, concentrations below LOQ were replaced by half of LOQ.Data plotted are arithmetic means.

1436 THE AMERICAN JOURNAL OF CARDIOLOGYT VOL. 83 MAY 15, 1999