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EFFECTS OF AVASIMIBE ON CYTOCHROME P450 2C9 EXPRESSION IN VITRO AND IN VIVO

Departments of Pharmacokinetics, Dynamics and Metabolism (J.S., K.A.R., L.S., N.S.), Experimental Medicine (R.H.S.), Clinical Pharmacokinetics and Pharmacodynamics (M.A.M.), and Molecular Biology (X.Z.), Pfizer Global Research and Development, Ann Arbor, Michigan; Clinical Studies Centers, LLC, Little Rock, Arkansas (G.G.); and Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina (S.J., D.G., E.L.L.)

Avasimibe, an acyl-CoA:cholesterol acyltransferase inhibitor, has been previously shown to be a potent inducer of CYP3A4 and multiple drug resistance protein 1. We have further characterized the drug interaction potential of avasimibe by studying the inductive and inhibitory effect of this compound on major drug-metabolizing enzymes. 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 ß-naphthoflavone as positive controls. No change was observed in CYP1A1/2 mRNA or activity levels after avasimibe treatment. Differential induction of CYP2C9- and CYP2B6-immunoreactive protein and activity was observed depending on drug concentration and donor. Microarray analysis showed a similar increase in CYP2C and CYP2B6 mRNA levels. The inhibition potential of avasimibe on the major drug-metabolizing enzymes was assessed using pooled human liver microsomes. Avasimibe inhibited CYP2C9 (IC₅₀ 2.9 µM), CYP1A2 (IC₅₀ 13.9 µM), and CYP2C19 (IC₅₀ 26.5 µM). A clinical drug interaction study was conducted to determine whether avasimibe might interact with the CYP2C9 substrate warfarin. 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. These results demonstrate that avasimibe's inductive spectrum resembles that of rifampin.

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