Slide 1EZT 2003-W-166091-SS

Mechanism of Action and Pharmacology of Ezetimibe

Copyright © 2003 MSP Singapore Company, LLC. All rights reserved.

Slide 2EZT 2003-W-166091-SS

Chemical Structure of Ezetimibe

Adapted from Catapano AL Eur Heart J Suppl 2001;3 (suppl E):E6-E10.

OH

OH

OF

N

F

Slide 3EZT 2003-W-166091-SS

Mechanism of Action of Ezetimibe

• Localizes at the brush border of the small intestine to prevent and

decrease the delivery

of intestinal cholesterol to the liver

• The reduction of hepatic cholesterol stores leads to an increase in

clearance of cholesterol from the blood

Adapted from van Heek M et al Br J Pharmacol 2000;129:1748-1754.

Slide 4EZT 2003-W-166091-SS

Metabolism of Ezetimibe

• Rapidly metabolized to an active glucuronide metabolite

• Both parent drug and metabolite inhibit cholesterol absorption

• Glucuronide metabolite more potent than parent drug in inhibiting cholesterol absorption

• Repeated enterohepatic circulation results in long duration of action

Adapted from Catapano AL Eur Heart J Suppl 2001;3(suppl E):E6-E10; van Heek M et al Br J Pharmacol 2000;129:1748-1754; Patrick JE et al Drug Metab Dispos 2002;30:430-437; Ezzet F et al Clin Ther 2001;23:871-885.

OHOGluc

OFN

F

Glucuronidation

Glucuronide

OHOH

OFN

F

Ezetimibe

Slide 5EZT 2003-W-166091-SS

Pharmacokinetics of Ezetimibe

• Elimination half-life of ezetimibe approximately 22 hours

• Enterohepatic recirculation of glucuronide metabolite

extends duration of action

• Long half-life

– Permits once-daily dosing

– Increases convenience

– May improve compliance

Adapted from Bays HE et al Clin Ther 2001;23:1209-1230; Kirsten R et al Clin Pharmacokinet 1998;34:457-482.

Slide 6EZT 2003-W-166091-SS

Adapted from Patrick JE et al Drug Metab Dispos 2002;30:430-437; Ezzet F et al Clin Ther 2001;23:871-885.

Ezetimibe: Summary ofPharmacokinetic Parameters

• Absorption– Rapid after oral administration– Peak plasma concentration in an average of 2–3 hours

• Distribution– Relative volume of distribution 107.5 L– 20% reabsorbed due to enterohepatic recirculation

• Elimination– Primarily in feces after extensive enterohepatic recirculation– Half-life 22 hours

Slide 7EZT 2003-W-166091-SS

Adapted from Data on file, MSD.

Factors Influencing Pharmacokinetics of Ezetimibe

• Food– No significant effect on oral bioavailability of ezetimibe

• Elderly– Plasma concentration of ezetimibe in elderly (65 years)

two-fold higher than in young (18–45 years)– Differences observed with age not clinically significant– Dosage adjustment not necessary

• Gender– Plasma concentration of ezetimibe slightly higher (<20%)

in women than in men– LDL-C reduction and safety profile comparable between men

and women– Dosage adjustment not necessary

Slide 8EZT 2003-W-166091-SS

Drug Interactions of Ezetimibe

• Ezetimibe does not induce cytochrome P450 enzymes• Statins: no significant pharmacokinetic interactions with

atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin• Other drugs: no effect on pharmacokinetics of dapsone,

dextromethorphan, digoxin, oral contraceptives, glipizide, tolbutamide, midazolam, or warfarin

• Cimetidine: no effect on bioavailability of ezetimibe• Antacids: decreased absorption rate of ezetimibe—not clinically significant• Cholestyramine: decreased mean AUC of ezetimibe ~55%

– May lessen incremental LDL-C reduction• Fibrates: safety and efficacy of fibrate co-administration

not established

Slide 9EZT 2003-W-166091-SS

Ezetimibe and Plasma LDL-C: Dose Response

SEM=standard error of the mean

*p<0.01 vs. placebo

Adapted from Bays HE et al Clin Ther 2001;23:1209-1230.

Mea

n %

ch

ang

e in

LD

L-C

Time (wk)

5

–5

–10

–15

–20

Baseline 2 4 6 8 10 Endpoint(±SEM)

0

12

Ezetimibe 0.25 mg (n=47)Ezetimibe 1 mg (n=49)Ezetimibe 5 mg (n=49)Ezetimibe 10 mg (n=46)Placebo (n=52)

**

**

Slide 10EZT 2003-W-166091-SS

Ezetimibe and Plasma LDL-C:Morning versus Evening Dosing

Mea

n %

ch

ang

e in

LD

L-C

fro

m b

asel

ine

at w

eek

12

AM dosing

5

–5

–10

–15

–20

0

*p<0.01 vs. placebo

Adapted from Bays HE et al Clin Ther 2001;23:1209-1230; Data on file, MSD.

Placebo(n=36)

+4.9

Ezetimibe5 mg (n=36)

–16.7*

Ezetimibe10 mg (n=39)

–17.5*

Ezetimibe5 mg (n=40)

–13.8*

PM dosing

Ezetimibe10 mg (n=38)

–18.2*

Slide 11EZT 2003-W-166091-SS

Key Benefits of Ezetimibe: Summary

• Unique mechanism of action inhibits absorption of dietary and biliary cholesterol

• Complements mechanism of action of cholesterol synthesis inhibitors (statins)

• Has additive LDL-C lowering effects with statins

• Pharmacokinetics– Long half-life permits once-daily dosing– No known clinically significant pharmacokinetic interactions

were seen with statins

• Provides greater lipid control when used in co-administration with statins

Slide 12EZT 2003-W-166091-SS

Before prescribing any of the products mentioned in this presentation,

please consult the manufacturers’ full prescribing information.