Transcript ENDOGENOUS AND EXOGENOUS SOURCES OF CHOLESTEROL

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Cholesterol Absorption
and the Mechanism
of Action of Ezetimibe
Slide 1
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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.
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Two Sources of Cholesterol:
Synthesis and Absorption
Dietary
cholesterol
Liver
(~300–700 mg/day)
Synthesis*
(~800 mg/day)
Biliary
cholesterol
(~1000 mg/day)
Extrahepatic
tissues
Absorption
(~700 mg/day)
Intestine
Fecal bile acids and neutral
sterols (~700 mg/day)
*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.
Slide 3
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% Cholesterol absorption
The Efficiency of Cholesterol Absorption
Regulates the Variation of Plasma
Cholesterol Levels
*
50
45
40
0
0
3.0
4.0
5.0
LDL-C (mmol/L)**
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.
Slide 4
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Cholesterol Absorption in the Intestine
300–700 mg
1000 mg
Resins
Plant stanols
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.
Slide 5
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Niemann-Pick C1 Like 1
OUT
IN
SSD
•
•
•
NPC1L1, identified in 2000, was a gene of unknown function related to NiemannPick 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
Adapted from Altmann SW et al Science 2004;303:1201–1204; Davis JP et al Genomics 2000;65:137–145.
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NPC1L1 Expression Localized
to the Surface of Enterocytes
Anti-NPC1L1
Relative level of NPC1L1 mRNA
100
Rat NPC1L1
Mouse NPC1L1
Human NPC1L1
10
0
Tissues
Rat jejunum
Adapted from Altmann SW et al Science 2004;303:1201–1204.
Slide 7
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Ezetimibe: Localization at Site
of Cholesterol Absorption
Absorption of cholesterol
in intestine (hamster)
Ezetimibe localization
at intestinal brush border (rat)
• 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.
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Metabolism of Ezetimibe
Ezetimibe
OH
OH
• Both parent drug and
metabolite inhibit cholesterol
absorption
N
F
O
Glucuronidation
F
OGluc
OH
N
F
Glucuronide
• Rapidly metabolized to an
active glucuronide metabolite
O
F
• 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.
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Cholesterol Absorption in NPC1L1 (–/–) Mice
and in (+/+) Mice Treated with Ezetimibe
% Cholesterol absorption
60
50
40
–69%
30
20
*
*
*
–/–
+/+
Ezetimibe
–/–
Ezetimibe
10
0
+/+
+/–
*p<0.001 vs. +/+ and +/–
+/+=wild-type mice; +/–=heterozygous mice; –/–=NPC1L1 null mice
Adapted from Altmann SW et al Science 2004;303:1201–1204.
Slide 10
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Effect of Ezetimibe on Atherogenesis
in Apolipoprotein E Knockout Mice*
Cross-sectional area of carotid arteries
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.
Slide 11
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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.
Slide 12
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Effect of Ezetimibe on Cholesterol
Absorption
% Cholesterol absorption
at week 2
80
54% Reduction in
cholesterol absorption
with ezetimibe
70
60
50
49.8%
40
30
22.7%
20
10
Individual absorption rates
Mean absorption rates
0
Placebo
Ezetimibe
Adapted from Sudhop T et al Circulation 2002;106:1943–1948.
Slide 13
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Effects of Ezetimibe on Plasma Lipids
Total
cholesterol
Mean % change from
baseline at 2 weeks
5
LDL-C
TG*
HDL-C
2.7
1.9
0.5
0
–5
–1.9
–5.2
–7.9
–10
–15
–20
–15.1**
–20.4**
–25
Placebo
Ezetimibe
HDL-C=high-density lipoprotein cholesterol
*Median values; **p<0.001
Adapted from Sudhop T et al Circulation 2002;106:1943–1948.
Slide 14
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Effect of Ezetimibe on Sterol Excretion
and Cholesterol Synthesis
Parameter, mg/day (mean ± SD)
3000
Placebo
Ezetimibe
+89%
p<0.001
+72%
p<0.001
2500
2000
1500
1000
+17%
p=0.068
+2%
p=0.776
500
0
307
313
Cholesterol
intake
999
1718
Neutral sterol
excretion
264
308
Acidic sterol
excretion
931
1763
Cholesterol
synthesis
Adapted from Sudhop T et al Circulation 2002;106:1943–1948.
Slide 15
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Effect of Ezetimibe Plasma Plant Sterols
–48%
p<0.001
Placebo
Ezetimibe
Sterol mg/dL (mean ± SD)
0.5
–41%
p<0.001
0.4
0.3
0.2
0.1
0.443
0.231
0.312
0.183
0.0
Compesterol
Sitosterol
Adapted from Sudhop T et al Circulation 2002;106:1943–1948.
Slide 16
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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
Adapted from Sudhop T et al Circulation 2002;106:1943–1948.
Slide 17
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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.
Slide 18
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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.
Slide 19
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References
Please see notes page.
Slide 20
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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 product
in any different manner than as described
in the prescribing information.
Copyright © 2004 MSP Singapore Company, LLC.
All rights reserved.
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Printed in USA
VISIT US ON THE WORLD WIDE WEB AT http://www.ezetrol.com
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