2.P.64 Biopharmaceutical profile of cerivastatin, a novel HMG-CoA reductase inhibitor

Tuesday 7 October Lipid-lowering

130 2.P.64

Biopbarmaceutical reductase inhibitor

profile

W. Muck’, K. Ochmann’ , A. Mazzu’, Pharmacology, Wuppertal, Germany: West Haven, USA

of cerivastotin,

a novel HMG-CoA

J. Lettieri* . ‘Bayer AG, Clinical 2Bayer Corp., Clinical Pharmacology,

Cerivastatin is a novel, synthetic, highly potent HMG-CoA reductase inhibitor that effectively reduces serum cholesterol levels at very low doses. During the world-wide clinical development of cerivastatin its biopharmaceutical properties have been assessed in a set of specifically designed clinico-pharmacological studies. Methods: Healthy young males, aged between 18 to 45 years, received cerivastatin tablets 50-400 fig as single- or multiple once-daily doses, in general under fasting conditions in the morning. Cerivastatin plasma concentrations were determined by validated specific HPLC assays employing post-column photochemical derivatisation and subsequent fluorescence detection Results: Cerivastatin distinguishes itself by: (a) rapid and complete absorption (298%, human mass-balance study of 400 Kg to four elderly males) with tmax at 2-3 h post-dose (b) plasma concentration/time profile of tablet identical to solution, i.e. relative bioavailability equals 100% (bioavailability study) (c) dose-proportionality in AUC and C,, from 50-400 fig with low intraand interindividual variability in pharmacokinetic parameters (singleand multiple-dose studies) (d) no influence of food on pharmacokinetics (single-dose study testing administration with high-fat meal and clinical investigations in patients) (e) no circadian effects on pharmacokinetics (singleand multiple dose qd/bid studies) (f) bioequivalence of marketed tablet strengths to drug formulations used in pivotal clinical trials (bioequivalence studies). Conclusion: Cerivastatin is a non-complicated drug with respect to its biopharmaceutical profile and bioavailability.

2.P.65 =

Stimulation HL-004

of bile acid production

by the ACAT

inhibitor

S. Mumkami, I. Yamagishi, M. Sato, K. Tomisawa, Y. Nara’, Y. Yamori’ Medicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd., Saitama; ‘Graduate School of Human and Environmental Studies, Kyoto University Kyoto, Japan Effects of a potent and specific acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor HL-004 on bile acid production were examined during the regression phase of pre-establised hypercholesterolemia. Stroke-prone spontaneously hypertensive rats (SHRSP) were fed a hypercholesterolemic diet for 30 days, then the diet was changed to one of normal chow (regression phase), and serum cholesterol levels were monitored for another 30 days. Bile acid secretion was examined in bile duct-cammlated SHRSP. HL-004 (0.09%) mixed in the normal chow was given to the rats during the 30 day regression phase. Decreases in serum cholesterol were accelerated following HL-004 ingestion. Bile acid secretion was also significantly stimulated by HL-004. HL-004 at 0.3-10 FM stimulated bile acid synthesis from [3H]cholesterol in HepG2 cells. The activity of hepatic cholesterol 7cr-hydroxylase, a rate limiting enzyme of bile acid synthesis, was significantly higher in HL-004 treated animals compared to findings in controls. Comparison of enzymatic activity, in the presence and absence of exogenous free cholesterol suggested that the higher enzymatic activity in the HL-004 treated group can be attributed to increases in endogenous free cholesterol, which may be the results of ACAT inhibition in the liver, and to a direct action of HL-004 on bile acid production. The stimulation of bile acid production by HL-004 may be related to the accelerated regression of hypercholesterolemia.

I2.P.66

1 Dose-related reduction of LDL-cholesterol in patients primary hypercholesterolemia by atorvastatin

Hamo Nakamura. Japan Cholesterol Lowering Group; National Defense. Tokorozawa, Japan

Atorvastatin

with

Study (J-CLAS)

The efficacy and safety of atorvastatin were studied in a double blind multicenter trial. Two hundred six patients with total cholesterol levels of 220 mg/dl or higher were randomly assigned to receive either 2.5, 5, 10 or 20 mg atorvastatin once daily for 12 weeks. Total and low density lipoprotein (LDL) cholesterol were reduced by 20% and 29% respectively with 2.5 mg, 25% and 32% respectively with 5 mg, I Ith International

Symposium

1997: Posters drugs 30% and 40% respectively with 10 mg, 34% and 49% respectively with 20 mg. Apolipoprotein B was reduced by 26% with 2.5 mg, 30% with 5 mg, 36% with 10 mg and 44% with 20 mg. Reductions of LDL cholesterol and apolipoprotein B were significantly correlated. LDL-triglycerides were reduced by 15% to 27% and LDL-phospholipids were decreased by 26% to 44% dose-dependently. Since major lipids in LDL and apolipoprotein B were reduced similarly, indicating the decrease in LDL particle numbers. Reductions in triglyceride were 6% to 20% unrelated to doses. Mild elevations in high density lipoprotein (HDL) cholesterol, especially in HDLz, were observed. HDLs cholesterol remained unchanged. Apolipoprotein A-I was increased by 6% to 9% and apolipoprotein A-II did not increase significantly. This would indicate LpA-I particle could be elevated by atorvastatn. Atorvastatin was well tolerated except a case complaining of transient dizziness and there were no serious adverse events or clinical laboratory abnormal ties.

1 2.P.67

1 Prolonged inhibition efficacy of atorvastatin

of cholesterol

synthesis

explains

the

R.P. Naoumova, S. Dunn, L. Rallidis, 0. Abu-Muhana, C. Neuwirth, mmG.W. Taylor’, G.R. Thompson. MRC Lipoprotein Team, Clinical Sciences Centre; ‘Department of Clinical Pharmacology, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK Atorvastatin, a newly-licensed compound, reportedly lowers low density lipoprotein (LDL) with greater efficacy than other statins. The mechanism of this action was therefore explored in twenty patients with refractory familial hyperchoiesterolaemia who received in a single-blind sequence simvastatin 40 mg/day, placebo and atorvastatin 10 mg/day each for 4 weeks. Administration of atorvastatin 10 mg daily lowered LDL cholesterol by 32.5% compared with placebo (P = 0.0001) which was 4.5% less than the decrease after simvastatin 40 mg daily (P = 0.33). At the end of the placebo period the effect of single 40 mg doses of simvastatin and atorvastatin on plasma levels and urinary excretion of mevalonic acid, indices of HMG CoA reductase activity, was compared. The area under the plasma curve and urinary mevalonic acid/creatinine ratio were both significantly less during the 24 hours after a single dose of atorvastatin 40 mg than after a single dose of simvastatin 40 mg (P < 0.01). These findings suggest that the greater efficacy of atorvastatin compared with simvastatin is due to more prolonged inhibition of HMG CoA reductase, presumably reflecting longer residence of atorvastatin or its active metabolites in the liver.

rxl

2 P 66

Difference in effect of simvastati cultured humau cell types

P. Negre-Aminou Laboratoz’PG,

on DNA

synthesis

among

M. van Erck, R.E.W. van Leeuwen, L.H. Cohen. Gaubius PO. Box 2215, 2301 CE Leiden, The Netherlands

Pravastatin (P), Lovastatin (L), Simvastatin (S), Atorvastatin (A), Fluvastatin (F) and Cerivastatin (C), all HMG-CoA reductase inhibitors, are used for treatment of hypercholesterolemia. As a result of cellular mevalonate depletion, these drugs also display anti-proliferative properties in cultured cells. We determined It&-values for proliferation for each drug in 4 human cell types: smooth muscle cells (HSMC), cornea fibroblasts (HCF), myoblasts from striated muscle and endothelial cells from umbilical vein. The inhibitory potencies were in the following order for all cell types: P
on Atherosclero.&

Paris,

October

1997