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Cholesterol Absorption and the Mechanism of Action of Ezetimibe


Ezetimibe: First New Therapy for Hyperlipidemia in 15 years

• Niacin, 1955

• Bile acid sequestrants, 1961

• Fibrates, 1967

• Statins (HMG-CoA reductase inhibitors), 1987

• Cholesterol absorption inhibitor (ezetimibe), 2002

Adapted from Bays H Expert Opin Investig Drugs 2002;11:1587–1604; Mahley RW, Bersot TP. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics 10th ed. New York: McGraw Hill, 2001:971–1002; Ginsberg HN, Goldberg IJ. In Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138–2149; Van Itallie TB et al N Eng J Med 1961;265:469–474; Altschul R et al Arch Biochem 1955;54:558–559.


Two Sources of Cholesterol: Synthesis and Absorption

Fecal bile acids and neutral sterols (~700 mg/day)

Extrahepatictissues

*And extrahepatic tissue

Adapted from Champe PC, Harvey RA. In Biochemistry. 2nd ed. Philadelphia: Lippincott Raven, 1994; Glew RH. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:728–777; Ginsberg HN, Goldberg IJ. In Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138–2149; Shepherd J Eur Heart J Suppl 2001;3(suppl E):E2–E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:1082–1150; Bays H Expert Opin Investig Drugs 2002;11:1587–1604.

BiliaryBiliarycholesterolcholesterol(~1000 mg/day)(~1000 mg/day)

Absorption(~700 mg/day)

LiverLiverSynthesis*Synthesis*(~800 mg/day)(~800 mg/day)

Intestine

DietaryDietarycholesterolcholesterol

(~300–700 mg/day)(~300–700 mg/day)


The Efficiency of Cholesterol Absorption Regulates the Variation of Plasma Cholesterol Levels

LDL-C=low-density lipoprotein cholesterol

*p<0.02 vs. lowest decile; **Number of subjects in each group is 14.

Adapted from Kesäniemi YA, Miettinen TA Eur J Clin Invest 1987;17:391–395.

LDL-C (mmol/L)**

0 3.0 4.0 5.0

% C

ho

lest

ero

l ab

sorp

tio

n

0

40

45

50 *


Cholesterol Absorption in the Intestine

1000 mg

NPC1L1

ACAT=acyl-coenzyme A:cholesterol acyltransferase; NPC1L1=Niemann-Pick C1 Like 1

Adapted from Champe PC, Harvey RA. In Biochemistry. 2nd ed. Philadelphia: Lippincott Raven, 1994; Ginsberg HN, Goldberg IJ. In Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138–2149; Shepherd J Eur Heart J Suppl 2001;3(suppl E):E2–E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:1082–1150;Davis JP et al Genomics 2000;65:137–145.

Resins

Plant stanols

300–700 mg


Niemann-Pick C1 Like 1

• NPC1L1, identified in 2000, was a gene of unknown function related to Niemann-Pick C1 protein

• DNA sequence analysis predicted features of a hypothetical cholesterol transporter– Membrane protein expressed on cell surface– Homologous to Niemann-Pick C1 (a protein known to be involved in cholesterol

movement)– Expression regulated by cholesterol– Sterol sensing domain

• Protein expression is restricted to the enterocytes of the proximal small intestine

SSD

OUT

IN

Adapted from Altmann SW et al Science 2004;303:1201–1204; Davis JP et al Genomics 2000;65:137–145.


NPC1L1 Expression Localized to the Surface of Enterocytes

Adapted from Altmann SW et al Science 2004;303:1201–1204.

Anti-NPC1L1

Rat jejunum

Rat NPC1L1Mouse NPC1L1Human NPC1L1

0

100

Rel

ati

ve

lev

el o

f N

PC

1L1

mR

NA

10

Tissues

Liver

Testis

Smal

l inte

stin

eG

all b

ladder

Heart

Stom

ach

Ova

ry

Lung

Musc

le

Colon

Brain

Kidney

Thyroid

Adrenal

Spleen


Ezetimibe: Localization at Site of Cholesterol Absorption

• Localizes at brush border of small intestine and prevents uptake of cholesterol into enterocytes

• Decreases delivery of intestinal cholesterol to liver resulting in– Up-regulation of LDL-C–receptor synthesis– Increased cholesterol clearance from the blood

Adapted from van Heek M et al Br J Pharmacol 2000;129:1748–1754; Brown WV Am J Cardiol 2001;87(suppl):23B–27B; Sparrow CP et al J Lipid Res 1999;10:1747–1757.

Absorption of cholesterolin intestine (hamster)

Ezetimibe localization at intestinal brush border (rat)


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 van Heek M et al Br J Pharmacol 2000;129:1748–1754; Patrick JE et al Drug Metab Dispos 2002;30:430–437.

OHOGluc

OFN

F

Glucuronidation

Glucuronide

OHOH

OFN

F

Ezetimibe


Cholesterol Absorption in NPC1L1 (–/–) Mice and in (+/+) Mice Treated with Ezetimibe

*p<0.001 vs. +/+ and +/–

+/+=wild-type mice; +/–=heterozygous mice; –/–=NPC1L1 null mice

Adapted from Altmann SW et al Science 2004;303:1201–1204.

0

10

60

% C

ho

lest

ero

l ab

sorp

tio

n

20

30

40

+/–+/+ +/+Ezetimibe

–/–Ezetimibe

50

–/–

* * *

–69%


Effect of Ezetimibe on Atherogenesis in Apolipoprotein E Knockout Mice*

Control Ezetimibe 5 mg/kg/day

*Mice fed 0.15% cholesterol diet for six months

Adapted from Catapano AL Eur Heart J Suppl 2001;3(suppl E):E6–E10; Davis HR Jr et al Arterioscler Thromb Vasc Biol 2001;21:2032–2038.

Cross-sectional area of carotid arteries


Cholesterol Absorption Study

• Randomized, double-blind, placebo-controlled, two-period, crossover trial

• Primary objective: to assess the effect of ezetimibe on intestinal cholesterol absorption

• Secondary objectives: to assess the effect of ezetimibe on cholesterol synthesis and plasma concentrations of noncholesterol sterols

• Subjects: 18 male patients with mild to moderate hypercholesterolemia

• Entry criteria – Age, 18–55 years– LDL-C, 3.4–4.7 mmol/L (130–180 mg/dL)– TG, <2.8 mmol/L (250 mg/dL)– Dietary cholesterol intake, 200–500 mg/day

TG=triglycerides

Adapted from Sudhop T et al Circulation 2002;106:1943–1948.


Effect of Ezetimibe on Cholesterol Absorption


0

10

20

30

40

50

70

8054% Reduction in cholesterol absorption with ezetimibe

Placebo

% C

ho

lest

ero

l ab

sorp

tio

n

at w

eek

2

Ezetimibe

60

49.8%

22.7%

Individual absorption ratesMean absorption rates


Effects of Ezetimibe on Plasma Lipids

HDL-C=high-density lipoprotein cholesterol

*Median values; **p<0.001


Mea

n %

ch

ang

e fr

om

b

asel

ine

at 2

wee

ks

PlaceboEzetimibe

LDL-C HDL-CTG*Total

cholesterol

–25

–20

–15

–10

–5

0

5

–1.9

–15.1**

1.9

–5.2

2.70.5

–7.9

–20.4**


Effect of Ezetimibe on Sterol Excretion and Cholesterol Synthesis


Par

amet

er, m

g/d

ay (

mea

n ±

SD

)

Cholesterolintake

Neutral sterolexcretion

Acidic sterolexcretion

Cholesterolsynthesis

500

1000

2000

0

2500

3000

+2%p=0.776

+89%p<0.001

1500

313307 1718999 264 1763931308

+72%p<0.001

+17%p=0.068

PlaceboEzetimibe


Effect of Ezetimibe Plasma Plant Sterols


PlaceboEzetimibe

0.0

0.1

0.5

Ste

rol

mg

/dL

(m

ean

± S

D)

Sitosterol

0.2

0.3

0.4

Compesterol

0.231 0.183

–41%p<0.001

–48%p<0.001

0.443 0.312


Cholesterol Absorption Study: Summary and Conclusions

• Treatment with ezetimibe 10 mg/day– Reduced intestinal cholesterol absorption by 54% vs. placebo– Reduced LDL-C by 20.4% vs. baseline– Reduced total cholesterol by 15.1% vs. baseline

• Reductions in plasma plant sterol levels with ezetimibe were more pronounced than reduction in cholesterol, possibly reflecting different absorption rates versus cholesterol or lack of endogenous synthesis

• Decrease in cholesterol absorption with ezetimibe was accompanied by an increase in cholesterol synthesis

• Increased cholesterol synthesis during ezetimibe administration underscores the potential value of dual inhibition of cholesterol absorption and synthesis with coadministration of ezetimibe with a statin



Ezetimibe: Summary of Pharmacokinetic Parameters

• Absorption– Rapidly absorbed after oral administration– Peak plasma concentration of active metabolite

in 1–2 hours• Elimination

– Eliminated principally in feces after extensive enterohepatic recirculation

– Elimination half-life of ~22 hours allows once-daily dosing• No induction of CYP 450 enzyme system• No significant pharmacokinetic interactions with commonly

used drugs• Bioavailability unaffected by food• Pharmacokinetics unaffected by age or gender

Adapted from Patrick JE et al Drug Metab Disp 2002;30:430–437; Summary of Product Characteristics, EZETROL™, MSP.


Key Benefits of Ezetimibe

• First of a new class of lipid-lowering drugs with unique mechanism of action– Inhibits absorption of dietary and biliary cholesterol– Reduces plasma LDL-C

• Coadministration with a statin provides Dual Inhibition of cholesterol absorption and cholesterol synthesis– Results in incremental improvement in LDL-C

compared with statin alone– Improves TG and HDL-C

• Favorable safety profile

Adapted from Ballantyne CM et al Circulation 2003;107:2409–2415; Bays H Expert Opin Investig Drugs 2002;11:1587–1604; Bays HE et al Clin Ther 2001;23:1209–1230; Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134; Gagné C et al Am J Cardiol 2002;90:1084–1091; Kerzner B et al Am J Cardiol 2003;91:418–424; Kosoglou T et al Br J Clin Pharmacol 2002;54:309–319; Leitersdorf E Eur Heart J Suppl 2001(Suppl E):E17–E23; Melani L et al Eur Heart J 2003;24:717–728; Shepherd J Eur Heart J Suppl 2001;3(Suppl E):E2–E5; Stein E Eur Heart J Supple 2001;3(Suppl E);E17–E23.


References

Please see notes page.


Cholesterol Absorption and the Mechanism of Action of Ezetimibe

Before prescribing, please consult the manufacturers’ prescribing information.

MSP does not recommend the use of any productin any different manner than as described

in the prescribing information.

Copyright © 2004 MSP Singapore Company, LLC.All rights reserved. 9-05 EZT 2004-W-6131-SS Printed in USA

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