Disease relevance of Avasimibe

• In conclusion, avasimibe is an ACAT inhibitor that has minimal adrenal effects in dogs, with dose-limiting toxicity defined by readily monitored and reversible changes in hepatic function [1].
• This study was designed to investigate the effects of avasimibe on human coronary atherosclerosis [2].
• Percent atheroma volume increased by 0.4% with placebo and by 0.7%, 0.8%, and 1.0% in the respective avasimibe groups (P=NS) [2].

High impact information on Avasimibe

• Avasimibe dose-dependently decreased ACAT activity in rat hepatocytes in the presence and absence of beta-migrating very low-density lipoproteins (betaVLDL) (by 93% and 75% at 10 micromol/L) and reduced intracellular storage of cholesteryl esters [3].
• Acyl-coenzyme A:cholesterol acyltransferase inhibitor, avasimibe, stimulates bile acid synthesis and cholesterol 7alpha-hydroxylase in cultured rat hepatocytes and in vivo in the rat [3].
• Avasimibe did not affect sterol 27-hydroxylase and oxysterol 7alpha-hydroxylase, 2 enzymes in the alternative pathway in bile acid synthesis [3].
• The ACAT inhibitor avasimibe reduces macrophages and matrix metalloproteinase expression in atherosclerotic lesions of hypercholesterolemic rabbits [4].
• We conclude that the bioavailable ACAT inhibitor avasimibe can directly limit macrophage accumulation, resulting in the histological appearance of mainly fibromuscular lesions, and can potentially stabilize preestablished atherosclerotic lesions by reducing MMP expression within the lesion [4].

Chemical compound and disease context of Avasimibe

• Toxicity was more closely associated with the exaggerated pharmacodynamic effects of the compound (e.g., marked serum cholesterol decreases) seen at the high doses of avasimibe used in these studies rather than with measures of systemic exposure (Cmax or AUC) [1].

Biological context of Avasimibe

• The present study was carried out in HepG2 cells to correlate the rate of cholesterol esterification and CE mass with apoB secretion by CI-1011, an acyl CoA:cholesterol acyltransferase (ACAT) inhibitor that is known to decrease apoB secretion, in vivo, in miniature pigs [5].
• Our results indicate that avasimibe causes clinically significant drug-drug interactions through direct activation of hPXR and the subsequent induction of its target genes CYP3A4 and multiple drug resistance protein 1 [6].
• Drug-drug interaction studies for CYP3A4 using pooled human hepatic microsomes and avasimibe at various concentrations, revealed IC50 values of 20.7, 1.6, and 3.1 microM using testosterone, midazolam, and felodipine as probe substrates, respectively [6].
• We hypothesized that coadministration of avasimibe and simvastatin would limit size, composition and extent of atherosclerotic lesions and potentially promote lesion regression, since bioavailable ACAT inhibitors decrease monocyte-macrophage enrichment and HMG-CoA reductase inhibitors limit smooth muscle cell migration and proliferation [7].
• Transient transfection assays showed that avasimibe is a potent activator of the human pregnane X receptor (hPXR) and more active than rifampin on an equimolar basis [6].

Anatomical context of Avasimibe

• Avasimibe reduced thoracic aortic and iliac-femoral CE content by 39%, the extent of thoracic aortic lesions by 41%, aortic arch cross-sectional lesions area by 35%, and monocyte-macrophage area by 27% [4].
• To examine the effect of CI-1011 on foam cell development, HMMs were incubated with aggregated acetylated LDL (ag-acLDL)+/-CI-1011 for 48 h [8].
• Subcellular fractionation of microsomes further confirmed the accumulation of secretion-incompetent apoB-lipoproteins in the endoplasmic reticulum (ER) and Golgi compartments of avasimibe-treated HepG2 cells [9].
• Treatment of cynomolgus monkey primary hepatocyte cultures with CI-1011 resulted in a dose-dependent inhibition of Lp(a) levels suggesting a direct hepatic effect of the compound [10].
• The inhibition potential of avasimibe on the major drug-metabolizing enzymes was assessed using pooled human liver microsomes [11].

Associations of Avasimibe with other chemical compounds

• In addition, other drugs, such as ezetimibe, colesevelam, torcetrapib, avasimibe, implitapide, and niacin are also being considered to manage hyperlipidemia [12].
• A 40% decrease in digoxin (P-glycoprotein substrate) area under the curve was observed with 750 mg of avasimibe daily for 10 days [6].
• Volunteers received 750 mg of avasimibe and showed a 54.2% reduction in trough concentrations of S-warfarin and decreased prothrombin times by 12, 15, 19, and 21% on days 6 through 9, respectively [11].
• In this study, we evaluated the effects of avasimibe, fluvastatin, and peroxisome proliferator-activated receptor (PPAR) ligands on 92-kDa gelatinase B (MMP-9) secretion by human THP-1 macrophages [13].
• Clinical data are scarce, but in a study performed in 130 men and women with combined hyperlipidemia and hypoalphalipoproteinemia, avasimibe, 50-500 mg/day, significantly reduced plasma total triglyceride and VLDL-cholesterol [14].

Gene context of Avasimibe

• Avasimibe, an acyl-CoA:cholesterol acyltransferase inhibitor, has been previously shown to be a potent inducer of CYP3A4 and multiple drug resistance protein 1 [11].
• Effects of avasimibe on cytochrome P450 2C9 expression in vitro and in vivo [11].
• Avasimibe inhibited CYP2C9 (IC50 2.9 microM), CYP1A2 (IC50 13.9 microM), and CYP2C19 (IC50 26.5 microM) [11].
• No change was observed in CYP1A1/2 mRNA or activity levels after avasimibe treatment [11].
• Enzymes known to be involved in the metabolism of drugs likely to be coadministered with avasimibe, such as CYP1A1/2, CYP2C, and CYP2B6, were evaluated further by microarray analysis, Western immunoblotting, and activity assays, using rifampicin and beta-naphthoflavone as positive controls [11].

Analytical, diagnostic and therapeutic context of Avasimibe

• One such agent, avasimibe, is in advanced clinical trials for the treatment of hyperlipidemia and atherosclerosis [15].
• Microarray analysis revealed avasimibe (1 microM) increased CYP3A4 mRNA 20-fold, compared with a 23-fold increase with 50 microM rifampin [6].
• Validated HPLC/MS/MS assay for CI-1011 in rat plasma and a comparison with an HPLC/UV assay [16].
• Amongst others, a very promising compound is Avasimibe, presently in phase III clinical trials as anti-hyperlipidemic and anti-atherosclerotic agent [17].
• Treatment with avasimibe resulted in a 92% reduction of lesion area compared with the HC control group [18].

References