Ezetimibe (Zetia) is the first cholesterol absorption inhibitor that can reduce low density lipoprotein cholesterol (LDL-C) either as monotherapy or in combination with HMG CoA reductase inhibitor (statin) therapy.1-4  It has been especially useful in helping some patients with significant hyperlipidemia to get to their individualized LDL-C goals when maximum doses of statins have been tried.5  In addition, ezetimibe can reduce the statin dose to tolerable levels in patients experiencing statin-related myopathy, while not losing LDL-C control.  Additional advantages include no significant drug interactions, overall good tolerability profile and being approved for once daily dosing. 

What is it about ezetimibe's pharmacokinetic profile that allows it to be dosed once daily and how does that impact its lipid lowering efficacy? 

• After oral administration, ezetimibe passes into the small intestine where it enters into the enterocyte and predominately undergoes glucuronidation by UGT1A1, UGT1A3 or UGT2B15 to form ezetimibe glucuronide (ezetimibe-G).6,7  Ezetimibe and ezetimibe-G are then transported via the portal circulation where much of it undergoes hepatic uptake before entering the systemic circulation.  Its hepatic uptake into the liver occurs via influx cell membrane transporters called, OATP1B1 (major) and OATP2B1 (minor).8  Upon entering the hepatocyte, any remaining ezetimibe (parent drug) will undergo glucuronidation and the resulting glucuronide metabolite will be excreted into the bile via the efflux cell membrane transporters MRP2 and P-glycoprotein (P-gp; MDR1).9  Upon its return to the small intestine ezetimibe-G will undergo enzymatic hydrolysis that puts the parent compound back in the intestinal lumen where this process will start again.10  This process is called enterohepatic recycling.  This recycling mechanism is what gives ezetimibe its long half life of 22 hours and the ability to be administered once daily.11  It also allows ezetimibe to continuously exert its inhibition of cholesterol absorption through the Niemann-Pick C1 Like 1 protein on the enterocyte.12  This process is also important for understanding why the lipid lowering efficacy does not change significantly with higher doses or more frequent dosage administration. 

Initial pharmacokinetic and pharmacodynamic studies revealed that ezetimibe's lipid lowering efficacy is dose dependent with reductions in LDL-C beginning to plateau after 5 mg once daily (LDL-C reductions relative to baseline; ezetimibe 0.25 mg (-12.7%); ezetimibe 1 mg (14.7%), ezetimibe 5 mg (15.8%); ezetimibe 10 mg (19.4%) and placebo (0%).13  It was also this study that assessed trough ezetimibe concentrations in association with LDL-C reductions where the majority of the patients were receiving the 10 mg dose and also had about 20% reductions in LDL-C.  In addition, ezetimibe concentrations were greater with certain medications (i.e., cyclosporine), as well as with older patients (greater than the age of 65 years) and those with severe liver disease.11,14  

All of these factors, especially the plateauing of the lipid lowering effects, support the rationale for giving 10 mg once daily and why giving multiple doses throughout the day is not likely to confer additional lipid lowering efficacy.

References:

1. Bays HE, Moore PB, Drehobl MA et al.  Effectiveness and tolerability of ezetimibe in patients with primary hypercholesterolemia: pooled analysis of two phase II studies.  Clin Ther  2001;23:1209-30.  
2. Davidson MH, McGarry T, Bettis R et al.  Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia.  J Am Coll Cardiol  2002;40:2125-34.  
3. Ballantyne CM, Houri J, Notarbartolo A et al.  Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial.  Circulation  2003;107:2409-15.  
4. Ballantyne CM, Blazing MA, King TR et al.  Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia.  Am J Cardiol  2004;93:1487-94.  
5. Feldman T, Koren M, Insull W Jr et al.  Treatment of high-risk patients with ezetimibe plus simvastatin co-administration versus simvastatin alone to attain National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol goals.  Am J Cardiol  2004;93:1481-6.  
6. Kosoglou T, Statkevich P, Johnson-Levonas AO et al.  Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions.  Clin Pharmacokinet  2005;44:467-94.  
7. Oswald S, Haenisch S, Fricke C et al.  Intestinal expression of P-glycoprotein (ABCB1), multidrug resistance associated protein 2 (ABCC2), and uridine diphosphate-glucuronosyltransferase 1A1 predicts the disposition and modulates the effects of the cholesterol absorption inhibitor ezetimibe in humans.  Clin Pharmacol Ther  2006;79:206-17.  
8. Oswald S, Konig J, Lutjohann D et al.  Disposition of ezetimibe is influenced by polymorphisms of hepatic uptake carrier OATP1B1.  Pharmacogenet Genomics  2008;18:559-68.  
9. Oswald S, Giessman T, Luetjohann D et al.  Disposition and sterol-lowering effect of ezetimibe are influenced by single-dose coadministration of rifampin, an inhibitor of multidrug transport proteins.  Clin Pharmacol Ther  2006;80:477-85.  
10. Van Heek M, France CF, Compton DS et al.  In vivo metabolism-based discover of a potent cholesterol absorption inhibitor, SCH58235, in the rat and rhesus monkey through the identification of the active metabolites of SCH48461.  J Pharmacol Exp Ther  1997;283:157-63.  
11. Ezetimibe (Zetia®) product package insert.  Merck/Schering-Plough Pharmaceuticals.  North Wales, PA.  May 2009.
12. Altmann SW, Davis HR Jr, Zhu LJ et al.  Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption.  Science  2004;303:1201-4. 
13. Ezzet F, Wexler D, Statkevich P et al.  The plasma concentrations and LDL-C relationship in patients receiving ezetimibe.  J Clin Pharmacol  2001;41:943-9. 
14. Busti AJ, Nuzum DS, Daves BJ, McKeever GC.  What is the mechanism by which the immunosuppressant, cyclosporine (Gengraf®, Sandimmune®, Neoral®) increases the cholesterol absorption inhibitor, ezetimibe (Zetia®), blood concentrations over 3-fold?  PW Drug Interact Newsl 2009;1(22):1-5.

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