Mechanism of Action and Pharmacology of Ezetimibe

1
Mechanism of Action and Pharmacology of Ezetimibe
2
Chemical Structure of Ezetimibe
Adapted from Catapano AL Eur Heart J Suppl 20013
(suppl E)E6-E10.
3
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
20001291748-1754.
4
Metabolism of Ezetimibe
Ezetimibe
OH

• 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

OH
N
F
O
Glucuronidation
F
Glucuronide
Adapted from Catapano AL Eur Heart J Suppl
20013(suppl E)E6-E10 van Heek M et al Br J
Pharmacol 20001291748-1754 Patrick JE et al
Drug Metab Dispos 200230430-437 Ezzet F et al
Clin Ther 200123871-885.
5
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
2001231209-1230 Kirsten R et al Clin
Pharmacokinet 199834457-482.
6
Ezetimibe Summary ofPharmacokinetic Parameters

• Absorption
• Rapid after oral administration
• Peak plasma concentration in an average of 23
  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

Adapted from Patrick JE et al Drug Metab Dispos
200230430-437 Ezzet F et al Clin Ther
200123871-885.
7
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 (1845
  years)
• Differences observed with age not clinically
  significant
• Dosage adjustment not necessary
• Gender
• Plasma concentration of ezetimibe slightly higher
  (lt20) in women than in men
• LDL-C reduction and safety profile comparable
  between men and women
• Dosage adjustment not necessary

Adapted from Data on file, MSD.
8
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
  ezetimibenot 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

9
Ezetimibe and Plasma LDL-C Dose Response
Ezetimibe 0.25 mg (n47) Ezetimibe 1 mg
(n49) Ezetimibe 5 mg (n49) Ezetimibe 10 mg
(n46) Placebo (n52)
5
0
5
Mean change in LDL-C

10

15


20
Baseline
2
4
6
8
10
Endpoint(SEM)
12
Time (wk)
SEMstandard error of the mean plt0.01 vs.
placebo Adapted from Bays HE et al Clin Ther
2001231209-1230.
10
Ezetimibe and Plasma LDL-CMorning versus
Evening Dosing
5
4.9
0
5
Mean change in LDL-C from baseline at week 12
10
15
20
Placebo (n36)
AM dosing
PM dosing
plt0.01 vs. placebo Adapted from Bays HE et al
Clin Ther 2001231209-1230 Data on file, MSD.
11
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

12
Before prescribing any of the products mentioned
in this presentation, please consult the
manufacturers full prescribing information.