Th-P16:374 Efficacy and safety of morning administration of fluvastatin extended release formulation is equivalent to evening administration

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P16

Thursday, June 22, 2006: Poster Session Plutrmacological control of lipids and lipoproteins

Th-P16:374 ] E F F I C A C Y A N D S A F E T Y O F M O R N I N G A D M I N I S T R A T I O N O F FLUVASTATIN E X T E N D E D R E L E A S E F O R M U L A T I O N IS E Q U I V A L E N T T O EVENING ADMINISTRATION H. Schaxnagl 1, M. Vogel 2 , C. Abletshauser 3 , F. Freisinger 1 , T. Stojakovic 1 , W. Maerz I . 1Medical Universi~, Graz, Austria." 2Astellas Pharma GmbH,

Munich, Germany." 3Novartis Pharma GmbH, NiitTtberg, Germany Fluvastatin is an inhibitor of HMG-CoA reductase and highly efficacious in the treatment of hypercholesterolemic patients. As the m a x i m u m of endogeneous cholesterol synthesis is during the night, it has been recommended that statins have to be taken once daily in the evening. In comparison to the immediate release formulation, fluvastatin 80 mg extended release O3R) formulation exhibits a longer mean residence time and may act longer on cholesterol synthesis. The present study compares the efficacy and safety of morning and evening administration of fluvastatin ER. In this double-blind, randomised, multicentre, parallel-group study 236 patients with type IIa/b hypercholesterolemia were randomized to receive fluvastatin E R 80 mg once daily in the morning or evening for 8 weeks. The effects of fluvastatin E R on the concentration of blood lipids and apolipoproteins were not significantly different between the morning and evening administration. Fluvastatin E R effectively lowered LDL-C by 34.5% in the morning treatment group and by 35.0% in the evening treatment group. Non-inferiority of morning administration compared with evening administration was statistically proven. Regarding triglycerides, there was a trend for greater reductions during morning administration (-23.1%) compared to evening administration (-16.6%) suggesting a higher impact on triglyceriderich lipoproteins when fluvastatin E R is given in the morning. HDL-C was increased by 9.4% (morning group) and by 6.3% (evening group). The treatment was well tolerated with a slightly lower frequency of adverse effects in the morning treatment group compared with the evening treatment group (27.4% vs 35.5%). The efficacy and safety of the morning administration of fluvastatin E R is equivalent to the conventional evening administration. Thus, the drug can be taken independently of daytime which may be more convenient for the patients.

T h - P 1 6 : 3 7 5 ] R O S U V A S T A T I N 5-20 M G IN J A P A N E S E H Y P E R T R I G L Y C E R I D E M I C PATIENTS: DOSE-RESPONSE STUDY Y. Sadto I , N. Yamada-, K. Shiral , J. Sasaki 4. 1Chiba Univ., Chiba, Japan: 2Univ. of Tsukuba, Tsukuba, Japan: 3Toho Univ., Sakura, Japan: 4bttemational Univ. of Health arm Welfare, Fukuoka, Japan Objectives: A dose-response study was conducted to assess effects of rosuvastatin (RSV) on triglycerides (TG) and other lipid parameters in Japanese patients. M e t h o d s : This was a placebo-controlled double-blind study. 154 patients with TG >200 and < 8 0 0 mg/dL were randomized to RSV 5, 10, or 20 mg once daily, placebo, or bezafibrate 200 mg twice daily (reference) for 8 weeks. Percent changes are reported as differences between RSV and placebo, and were assessed by analysis of variance. Results: In the placebo comparison, no apparent dose response was seen for TG reductions and high-density lipoprotein cholesterol (HDL-C) enhancement, but an apparent dose response was observed for other parameters. TG was reduced by 30.1% with RSV 5 rag, 30.1% with 10 rag, and 32.3% with 20 mg (all P_<0.0001). RSV was associated with large dose-related reductions in non-HDL-C (38.1% to 45.6%), low-density lipoprotein cholesterol (LDL-C) (35.5% to 44.6%), total cholesterol (TC) (28.4% to 34.7%), and large increases in HDL-C (10.7% to 15.0%). Compared with bezafibrate, RSV showed a trend towards producing smaller improvements in TG and HDL-C but greater improvements in other parameters. RSV across its dose ranges reduced TG by 29.1% to 31.1% from baseline, compared with 45.4% for bezafibrate. RSV was well tolerated. Conclusions: Compared with placebo, RSV 5-20 mg produces significant decreases in TG in Japanese hypertriglyceridemic patients without evidence of a dose response. However, apparent dose response of non-HDL-C, LDL-C and TC suggests increased benefit with increasing doses. Funding: This study was supported financially by AstraZeneca.

IT h - P 1 6 : 3 7 6 1

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ABCG5/8 AND NPC1L1 POLYMORPHISMS AND R E S P O N S E T O PRAVASTATIN IN P R O S P E R

E. Polisecki 1, A. Gaw 2, J. Shepherd 2, E.J. Schaefer I . 1Cardiovascular

Research Laboratory, T~ts University, Boston, MA, USA." 2Department of Pathological Biochemistt T, Glasgow, United Kingdom PROSPER was a study in which 5804 men and women (mean age 75 years) with or without vascular disease were randomized to placebo or pravastatin 40 mg/day and followed for a mean of 3.2 years. Coronary heart disease (CHD) death and non fatal myocardial infarction were reduced by 19% (p=0.006), a 30% estimated reduction over 5 years. We axe investigating the genetic bases of the variability in LDL lowering (mean -34%) in response to pravastatin, and genetic variation in CHD risk reduction. We have previously documented that LDL cholesterol lowering variability in response to the simvastatin/niacin combination relates to changes in plasma beta sitosterol, suggesting that statins can uppregulate intestinal cholesterol absorption. We have therefore evaluated 5 single nucleotide polymorphisms (SNPs) at the ABCG5/8 genes and 6 SNPs at the NPC1L1 gene in all PROSPER participants in order to test the hypothesis that variability at these gene loci can affect variation in LDL lowering, changes in plasma sterols, and CHD risk reduction. Our preliminary data indicates that the presence of the ABCG8 D 19H variant, found in 7.1% of the population, results in a significantly greater LDL cholesterol lowering response to pravastatin than other genotypes. Our data set on ABCG5/8 and NPC1L1 SNPs will be presented at the meeting. Our data are consistent with the concept that genetic variation at these gene loci aYfects intestinal cholesterol absorption, LDL lowering response to statins, and CHD risk reduction. Hyporesponders to statins may therefore be ideal candidates for ezetimibe treatment to decrease intestinal cholesterol absorption.

IT h - P 1 6 : 3 7 7 1

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THE EFFECT OF GRAPEFRUIT JUICE C O N S U M P T I O N O N M E T A B O L I S M O F STATINS IN PATIENTS WITH PRIMARY DYSLIPIDEMIA

H. Paschalidou, A. Efthimiadis, I. Efthimiadis, M. Raptopoulou-Gigi. Lipid

Clinic, _rid bttemal Medicine Department, Hippocration Hospital, Thessaloniki, Greece Objectives: To study the effect of grapefruit juice consumption in patients who received lipophilic statin therapy for the management of primary dyslipidemia. M e t h o d s : 30 patients were treated (aged 454-4.5 years) with lovastatin 40 rag/day for the management of primary dyslipidemia. All patients had been tolerating the medication well. The last 6 months 12 of them presented with fatigue, weakness and muscle pain. Clinical examination was negative. The patients" history, revealed grapefruit juice (200 ml) consumption once daily the same time. Results: In all patients there was improvement of the lipidemic profile. Total cholesterol was reduced by 20-28%, triglycerides by 24-28%, LDL by 31-34%, and HDL was increased by 6-8%. Liver enzymes (SGOT, SGPT) and creatine kinase (CK) levels were normal in the patients who received only lovastatin. In the subgroup, who consumed grapefruit juice the same time with lovastatin therapy, was observed a 20-fold increase in levels of liver enzymes and creatine kinase levels were 2200-3000 IU/L. There was immediate discontinuance of drug and grapefruit juice. Laboratory examination of liver and renal function was held daily. We excluded other systemic diseases and we observed daily the CK levels. In a week, all biochemical markers came at normal levels. C o n d u s i o n : Lipophilic statins undergo cytochrome P450 oxidative metabolism, especially by the isoenzyme CYP3A4. Grapefruit juice is also metabolized by the same cytochrome. Co-administration of grapefruit juice and lipophilic statins increases drugs" levels causes toxic effects in liver and muscle function and must be avoided.

ITh-P16:3781 LOOF WT RHADNLS PCLHAONLTE SVTAESRCOULL OPPRAETDHI CYTINS TPHE DE IOANT RS EI CT I i

C A R D I A C R E C I P I E N T S O N PRAVASTATIN THERAPY M. Hedman I , R. PaJalman 2, J. Sundvall 2 , C. Ehnholm 2 , M. Syv/inne 3 , E. Jokinen 1 , M. Jauhiamen-, C. Holmberg I , M. AntikaJnen 1 . 1 Hospital for

Children and Adolescents, Helsinki, Finland: 2National Public Health btstitute, Helsinki, Finland; - Division of Cardiology, Universi~ of Helsinki, Helsbtki, Finland Objective: Transplant coronary artery disease (TxCAD) is the main cause of poor long-term survival among pediatric cardiac transplant recipients(CTR). We investigated lipoprotein levels and composition of lipoprotein particles

XIV bztetTtational Symposium on Atherosclerosis, Rome, Italy, June 18-22, 2006