Hello, astounder-ga!
Congratulations on your upcoming presentation. That sounds like a big step!
I have compiled the answers to your multi-part question about
Ezetimibe in an attempt to help you look brilliant and smart when
presenting your information. Most of it is fairly cut and dried, as
I'm sure you are aware. I have also posted references to some relevant
slides which provide a more simplified explanation and which may add a
little zing to your presentation! I have included information from a
variety of sources so you can decide which references are most
comfortable for you to use.
================================
GENERAL BACKGROUND - EZETIMIBE
================================
Ezetimibe (also known as ZETIA) is used alone or in conjunction with
statin drugs to help lower the absorption of cholesterol from the
digestive tract.
Some simplified explanations about Exetimibe follow:
From "ZETIA (ezetimibe) Named Cardiovascular Compound of the Year at
2004 Pharmaceutical Achievement Awards." Medical News Today. 15 Aug
2004
http://www.medicalnewstoday.com/medicalnews.php?newsid=12083
"ZETIA is the first in a class of cholesterol-lowering therapies that
works by blocking cholesterol absorption in the intestine. Clinical
studies have demonstrated that adding ZETIA to a statin provides
significant additional LDL cholesterol-lowering efficacy through dual
inhibition of cholesterol production in the liver and absorption in
the intestine. ZETIA, along with diet, is indicated for use either by
itself or together with statins in patients with high cholesterol to
reduce LDL cholesterol and total cholesterol when the response to
diet and exercise has been inadequate."
=
From Medicine.net
http://www.medicinenet.com/ezetimibe/article.htm
"Ezetimibe is a drug that is used for the treatment of elevated blood
cholesterol levels. It is estimated that sixty percent of the 13
million patients who are already taking drugs for elevated cholesterol
levels continue to have LDL cholesterol ("bad" cholesterol) higher
than recommended levels. Ezetimibe lowers blood cholesterol by
blocking the absorption of cholesterol, including dietary cholesterol,
from the intestines. It does not affect, however, the absorption of
triglycerides or fat-soluble vitamins. Ezetimibe was approved by the
FDA in October, 2002."
=
From Zetia.com:
http://www.zetia.com/ezetimibe/zetia/consumer/how_it_works/index.jsp?mtc=5LEFT
Excerpt:
"ZETIA works in a manner unique to cholesterol medications in the way
it reduces the amount of cholesterol that is absorbed from the
digestive tract. If you?re taking a statin and still not at your
cholesterol goal, ask your doctor if adding ZETIA, along with dieting,
can help you reach your LDL (Bad) Cholesterol goal. If you?re taking a
statin, ZETIA can boost your results when added to your current
therapy."
"You may find it helpful to know that cholesterol comes from 2
sources. It?s produced naturally in your body, and it?s found in the
food you eat. What you may not know is that the amount of LDL (Bad)
Cholesterol in your blood is controlled in 2 important places:
* Your liver - which produces cholesterol and uses it to make digestive (or
bile) acids.
* Your digestive tract - which absorbs cholesterol both from food and from
bile made by the liver.
"A statin works in the liver to lower LDL (Bad) Cholesterol. ZETIA
lowers LDL (Bad) Cholesterol in a different way. It works in the
digestive tract to reduce the absorption of cholesterol. So, if you
are dieting and taking a statin, adding ZETIA can help lower LDL (Bad)
Cholesterol even further. If you?re not taking a statin, ZETIA along
with diet and exercise is still an effective way to reduce your LDL
(Bad) Cholesterol if diet alone has not lowered your cholesterol
enough."
=
Also see "What Zetia Does."
http://www.zetia.com/ezetimibe/zetia/consumer/what_it_does/index.jsp
=
** See Slide from Lipids Online: "Ezetimibe."
http://www.lipidsonline.org/slides/slide01.cfm?q=ezetimibe&dpg=3
==================================
FORMULATION/CHEMICAL COMPOSITION
==================================
From the FDA website:
http://www.fda.gov/cder/foi/label/2002/21445lbl.pdf
"ZETIA (ezetimibe) is in a class of lipid-lowering compounds that
selectively inhibits the intestinal absorption of cholesterol and
related phytosterols. The chemical name of ezetimibe is
1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone.
The empirical formula is C24H21F2NO3. Its molecular weight is 409.4
and its structural formula is (see reference for diagram)."
"Ezetimibe is a white, crystalline powder that is freely to very
soluble in ethanol, methanol, and acetone and practically insoluble in
water. Ezetimibe has a melting point of about 163°C and is stable at
ambient temperature. ZETIA is available as a tablet for oral
administration containing 10 mg of ezetimibe and the following
inactive ingredients: croscarmellose sodium NF, lactose monohydrate
NF, magnesium stearate NF, microcrystalline cellulose NF, povidone
USP, and sodium lauryl sulfate NF."
====================
MECHANISM OF ACTION
====================
From the FDA website:
http://www.fda.gov/cder/foi/label/2002/21445lbl.pdf
"Ezetimibe reduces blood cholesterol by inhibiting the absorption of
cholesterol by the small intestine."
"The cholesterol content of the liver is derived predominantly from
three sources. The liver can synthesize cholesterol, take up
cholesterol from the blood from circulating lipoproteins, or take up
cholesterol absorbed by the small intestine. Intestinal cholesterol is
derived primarily from cholesterol secreted in the bile and from
dietary cholesterol."
"Ezetimibe has a mechanism of action that differs from those of other
classes of cholesterol-reducing compounds (HMG-CoA reductase
inhibitors, bile acid sequestrants [resins], fibric acid derivatives,
and plant stanols). Ezetimibe does not inhibit cholesterol synthesis
in the liver, or increase bile acid excretion. Instead, ezetimibe
localizes and appears to act at the brush border of the small
intestine and inhibits the absorption of cholesterol, leading to a
decrease in the delivery of intestinal cholesterol to the liver. This
causes a reduction of hepatic cholesterol stores and an increase in
clearance of cholesterol from the blood; this distinct mechanism is
complementary to that of HMG-CoA reductase inhibitors."
=
* See Slide from Lipids Online - "Ezetimimbe - Mechanism of Action."
http://www.lipidsonline.org/slides/slide01.cfm?q=ezetimibe&dpg=10
=
* See Slide showing the mechanism of action of Ezetimibe in the
intestines, see the slide titled "Mechanism of Therapeutic Agents" in
the following report: "Getting to Goal - Combination Terapy for the
Management of Dyslipidemias," by Freny Vaghaiwalla Mody, MD. June 14,
2004.
http://www.aanp.org/NR/rdonlyres/e4uqo23amnvk4izqm7l5h4yqevfrvutxhtzngnqzypidimbqtzfdp7zmzej4r545beb6gdxpisgunk/mody+bio+%2526+slides.pdf
==
From "Ezetimibe (Zetia)" by Bernadette A. Clark. Pharmacotherapy
Update. Vol. VI, No 11. March/April 2003.
http://www.clevelandclinicmeded.com/medical_info/pharmacy/marapr2003/ezetimibe.htm
"Bile acid sequestrants (e.g., cholestyramine) bind bile acids
inhibiting their reabsorbtion. In turn, to produce more bile acids,
the liver breaks down cholesterol. Similar to bile acid sequestrants,
ezetimibe also acts in the small intestine. After oral administration,
it is glucuronidated to an active metabolite (ezetimibe glucuronide),
travels through the portal vessels to the bile, and is then brought
back to the small intestine via enterohepatic recycling. When food is
ingested, ezetimibe is excreted with the bile and acts at the brush
border of the small intestine to inhibit the uptake of dietary and
biliary cholesterol into the enterocytes. Furthermore, there is no
inhibition of cholesterol synthesis in the liver or increase in bile
acid secretion."
============================
ABSORPTION AND DISTRIBUTION
============================
From the FDA website:
http://www.fda.gov/cder/foi/label/2002/21445lbl.pdf
"After oral administration, ezetimibe is absorbed and extensively
conjugated to a pharmacologically active phenolic glucuronide
(ezetimibe-glucuronide). After a single 10-mg dose of ZETIA to fasted
adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5
ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide
mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours
(Tmax). There was no substantial deviation from dose proportionality
between 5 and 20 mg. The absolute bioavailability of ezetimibe cannot
be determined, as the compound is virtually insoluble in aqueous media
suitable for injection. Ezetimibe has variable bioavailability; the
coefficient of variation, based on inter-subject variability, was 35
to 60% for AUC values."
Effect of Food on Oral Absorption - "Concomitant food administration
(high fat or non-fat meals) had no effect on the extent of absorption
of ezetimibe when administered as ZETIA 10-mg tablets. The Cmax value
of ezetimibe was increased by 38% with consumption of high fat meals.
ZETIA can be administered with or without food."
Distribution - "Ezetimibe and ezetimibe-glucuronide are highly bound
(>90%) to human plasma proteins."
==========================
METABOLISM AND EXCRETION
==========================
From the FDA website:
http://www.fda.gov/cder/foi/label/2002/21445lbl.pdf
"Ezetimibe is primarily metabolized in the small intestine and liver
via glucuronide conjugation (a phase II reaction) with subsequent
biliary and renal excretion. Minimal oxidative metabolism (a phase I
reaction) has been observed in all species evaluated."
"In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide.
Ezetimibe and ezetimibe-glucuronide are the major drug-derived
compounds detected in plasma, constituting approximately 10 to 20% and
80 to 90% of the total drug in plasma, respectively. Both ezetimibe
and ezetimibe-glucuronide are slowly eliminated from plasma with a
half-life of approximately 22 hours for both ezetimibe and
ezetimibe-glucuronide. Plasma concentration-time profiles exhibit
multiple peaks, suggesting enterohepatic recycling."
"Following oral administration of 14C-ezetimibe (20 mg) to human
subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide)
accounted for approximately 93% of the total radioactivity in plasma.
After 48 hours, there were no detectable levels of radioactivity in
the plasma."
"Approximately 78% and 11% of the administered radioactivity were
recovered in the feces and urine, respectively, over a 10-day
collection period. Ezetimibe was the major component in feces and
accounted for 69% of the administered dose, while
ezetimibe-glucuronide was the major component in urine and accounted
for 9% of the administered dose."
=
* See Slide from Lipids Online: "Ezetimibe: metabolism."
http://www.lipidsonline.org/slides/slide01.cfm?q=ezetimibe&dpg=16
====================
THERAPEUTIC ASPECTS
====================
From Physician's Handout on Zetia/Ezetimibe Tablets."
http://www.zetia.com/zetia/shared/documents/zetia_pi.pdf
"ZETIA, administered alone, is indicated as adjunctive therapy to diet
for the reduction of elevated total-C, LDL-C, and Apo B in patients
with primary (heterozygous familial and non-familial)
hypercholesterolemia."
Combination Therapy with HMG-CoA Reductase Inhibitors:
"ZETIA, administered in combination with an HMG-CoA reductase
inhibitor, is indicated as adjunctive therapy to diet for the
reduction of elevated total-C, LDL-C, and Apo B in patients with
primary (heterozygous familial and non-familial)
hypercholesterolemia."
Homozygous Familial Hypercholesterolemia (HoFH):
"The combination of ZETIA and atorvastatin or simvastatin, is
indicated for the reduction of elevated total-C and LDL-C levels in
patients with HoFH, as an adjunct to other lipid-lowering treatments
(e.g., LDL apheresis) or if such treatments are unavailable.
Homozygous Sitosterolemia:
"ZETIA is indicated as adjunctive therapy to diet for the reduction
of elevated sitosterol and campesterol levels in patients with
homozygous familial sitosterolemia."
==
* See Side from Lipids Online: "Ezetimibe: Indications."
http://www.lipidsonline.org/slides/slide01.cfm?q=ezetimibe&dpg=19
====================================
ADVERSE REACTIONS/DRUG INTERACTIONS
====================================
Potential Adverse Reactions from various references are listed below:
From "Ezetimibe (Zetia)" by Bernadette A. Clark. Pharmacotherapy
Update. Vol. VI, No 11. March/April 2003.
http://www.clevelandclinicmeded.com/medical_info/pharmacy/marapr2003/ezetimibe.htm
"Overall, ezetimibe is well tolerated. When used as monotherapy, the
most commonly reported adverse effect is back pain (4.1%). In the
majority of the studies, the adverse effects associated with ezetimibe
were similar to placebo. Additionally, when it is used in combination
with a statin, ezetimibe has a side effect profile similar to statin
monotherapy. When ezetimibe was administered with a statin, there was
a slight increase in the incidence of elevated transaminases compared
to statin monotherapy."
==
From "Ezettimibe." Medline Plu
http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a603015.html
Potential side effects include:
headache
diarrhea
dizziness
sore throat
runny nose
sneezing
joint pain
muscle pain
==
For a more serious clinical evaluation of adverse reactions noted in
patients taking Zetia versus placebo, see charts 8 and 9 under the
heading "Adverse Reactions"in the following physician's handout for
Zetia:
http://www.zetia.com/zetia/shared/documents/zetia_pi.pdf
==
Muscle Disorders
-----------------
From "Ezetimibe, muscle link highlighted," by Bianca Nogrady.
Australian Doctor 10-Aug-2005
http://news.australiandoctor.com.au/articles/cf/0c0352cf.asp
"CONCERNS about muscle disorders linked to the lipid-lowering drug
ezetimibe (Ezetrol) have been flagged in the latest Australian Adverse
Drug Reactions Bulletin. The Adverse Drug Reactions Advisory Committee
drew attention to side effects such as myalgia, muscle cramps,
weakness and pain associated with the drug in the August edition of
the bulletin. Forty-four incidents of muscle disorders have been
reported to ADRAC since ezetimibe was registered in June 2003. In
almost half of cases, the symptoms developed within two weeks of
starting the medication. Twenty-one patients had a history of muscle
disorders or increased creatine kinase associated with statin use.
Myalgia and myopathy are listed as possible adverse effects of
ezetimibe when used with statins."
=
For updated warnings about adverse reactions, see:
"Subject: Association of Ezetrol® (ezetimibe) with myalgia,
rhabdomyolysis, hepatitis, pancreatitis, and thrombocytopenia." Merck
Frosst/Schering Pharmaceuticals. Feb 1, 2005
http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/ezetrol_hpc-cps_e.html
"The Warnings, Precautions, and Adverse Events sections are being
updated to reflect the occurrence of the following adverse events in
patients taking Ezetrol® (ezetimibe) alone or in combination with a
statin:
myalgia;
rhabdomyolysis;
hepatitis;
acute pancreatitis;
thrombocytopenia; and
suspected interaction between Ezetrol® (ezetimibe) and warfarin."
==
Some of the drug intereactions listed on RXList follow:
http://www.rxlist.com/cgi/generic/ezetimibe_cp.htm
ZETIA had no significant effect on a series of probe drugs (caffeine,
dextromethorphan, tolbutamide, and IV midazolam) known to be
metabolized by cytochrome P450 (1A2, 2D6, 2C8/9 and 3A4) in a
"cocktail" study of twelve healthy adult males. This indicates that
ezetimibe is neither an inhibitor nor an inducer of these cytochrome
P450 isozymes, and it is unlikely that ezetimibe will affect the
metabolism of drugs that are metabolized by these enzymes.
Warfarin: "Concomitant administration of ezetimibe (10 mg once daily)
had no significant effect on bioavailability of warfarin and
prothrombin time in a study of twelve healthy adult males."
Digoxin: "Concomitant administration of ezetimibe (10 mg once daily)
had no significant effect on the bioavailability of digoxin and the
ECG parameters (HR, PR, QT, and QTc intervals) in a study of twelve
healthy adult males."
Gemfibrozil: "In a study of twelve healthy adult males, concomitant
administration of gemfibrozil (600 mg twice daily) significantly
increased the oral bioavailability of total ezetimibe by a factor of
1.7. Ezetimibe (10 mg once daily) did not significantly affect the
bioavailability of gemfibrozil."
Oral Contraceptives: "Co-administration of ezetimibe (10 mg once
daily) with oral contraceptives had no significant effect on the
bioavailability of ethinyl estradiol or levonorgestrel in a study of
eighteen healthy adult females."
Cimetidine: "Multiple doses of cimetidine (400 mg twice daily) had no
significant effect on the oral bioavailability of ezetimibe and total
ezetimibe in a study of twelve healthy adults."
Antacids: "In a study of twelve healthy adults, a single dose of
antacid (SupraloxTM 20 mL) administration had no significant effect on
the oral bioavailability of total ezetimibe, ezetimibe-glucuronide, or
ezetimibe based on AUC values. The Cmax value of total ezetimibe was
decreased by 30%."
Glipizide: "In a study of twelve healthy adult males, steady-state
levels of ezetimibe (10 mg once daily) had no significant effect on
the pharmacokinetics and pharmacodynamics of glipizide. A single dose
of glipizide (10 mg) had no significant effect on the exposure to
total ezetimibe or ezetimibe."
HMG-CoA reductase inhibitors: "In studies of healthy
hypercholesterolemic (LDL-C ³130 mg/dl) adult subjects, concomitant
administration of ezetimibe (10 mg once daily) had no significant
effect on the bioavailability of either lovastatin, simvastatin,
pravastatin, atorvastatin, or fluvastatin. No significant effect on
the bioavailability of total ezetimibe and ezetimibe was demonstrated
by either lovastatin (20 mg once daily), pravastatin (20 mg once
daily), atorvastatin (10 mg once daily), or fluvastatin (20 mg once
daily)."
Fenofibrate: "In a study of thirty-two healthy hypercholesterolemic
(LDL-C ³130 mg/dl) adult subjects, concomitant fenofibrate (200 mg
once daily) administration increased the mean Cmax and AUC values of
total ezetimibe approximately 64% and 48%, respectively.
Pharmacokinetics of fenofibrate were not significantly affected by
ezetimibe (10 mg once daily)."
Cholestyramine: "In a study of forty healthy hypercholesterolemic
(LDL-C ³130 mg/dl) adult subjects, concomitant cholestyramine (4 g
twice daily) administration decreased the mean AUC values of total
ezetimibe and ezetimibe approximately 55% and 80%, respectively."
==
* See Slide from Lipids Online: "Ezetimibe: drug interactions."
http://www.lipidsonline.org/slides/slide01.cfm?q=ezetimibe&dpg=18
* See Slide from Lipids Online: Ezetimibe: Contraindications."
http://www.lipidsonline.org/slides/slide01.cfm?q=ezetimibe&dpg=20
============================================
ADDITIONAL "RAZZLE-DAZZLE" IF YOU WANT IT!
============================================
"Higher-Dose Ezetimibe to Treat Homozygous Sitosterolemia." Sponsored
by National Heart, Lung, and Blood Institute (NHLBI). Clinical
Trials.gov. December 14, 2004.
http://www.clinicaltrials.gov/ct/gui/show/NCT00099996
"This study will test the safety and effectiveness of 40 mg of
ezetimibe (Zetia ) daily in lowering blood levels of cholesterol and
of the plant sterols sitosterol and campesterol in patients with
homozygous sitosterolemia, an inherited disorder of sterol
metabolism.......Current treatment consists of ezetimibe 10 mg,
dietary restriction of plant and shellfish sterols, and bile salt
binding resins."
=
"Efficacy and safety of ezetimibe co-administered with simvastatin in
thiazolidinedione-treated type 2 diabetic patients." Authors: L. M.
Gaudiani1; A. Lewin2; L. Meneghini3; I. Perevozskaya4; D. Plotkin4; Y.
Mitchel4; S. Shah4
Source: Diabetes, Obesity and Metabolism, Volume 7, Number 1, January
2005, pp. 88-97(10) http://www.ingentaconnect.com/content/bsc/dom/2005/00000007/00000001/art00012
Conclusions: "Co-administration of ezetimibe with simvastatin, a dual
inhibition treatment strategy targeting both cholesterol synthesis and
absorption, is well tolerated and provides greater LDL-C-lowering
efficacy than increasing the dose of simvastatin in T2DM patients
taking TZDs."
=
"The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1)." PNAS |
June 7, 2005 | vol. 102 | no. 23 | 8132-8137.
http://www.pnas.org/cgi/content/abstract/102/23/8132
Results - "unequivocally establish NPC1L1 as the direct target of
ezetimibe and should facilitate efforts to identify the molecular
mechanism of cholesterol transport."
==
"CASE REPORT = Ezetimibe-induced hyperlipidaemia." E. Doherty, P. J.
Lumb, G. Chik, A. S. Wierzbicki. International Journal of Clinical
Practice. Volume 59 Issue s147 Page 3 - April 2005
http://www.blackwell-synergy.com/links/doi/10.1111/j.1368-504X.2005.00423.x/abs/?cookieSet=1
"Ezetimibe is intestinally active cholesterol absorption inhibitor
used to reduce low-density lipoproteincholesterol levels. This case
report describes a novel side effect with this agent:
ezetimibe-induced hyperlipidaemia in a patient with statin intolerance
and familial combined hyperlipidaemia. Ezetimibe therapy induced an
asymptomatic 770% increase in triglycerides (TGs) (3.5127.1 mmol/l)
and a 190% increase in total cholesterol (9.818.5 mmol/l) secondary to
an increase (4.625.9 µmol/l; 560%) in hepatic cholesterol
(lathosterol) synthesis. This lipid profile resolved 9 months after
cessation of ezetimibe therapy. This report shows that ezetimibe may
have long-lasting effects in man far exceeding its plasma half-life
and that ezetimibe monotherapy can induce a large increase in
hepatocyte very-low-density lipoprotein synthesis in rare individuals
with a consequent mixed hyperlipidaemia or possibly
hypercholesterolaemia depending on the metabolism and clearance of
TG-rich lipoproteins."
=
"Drug-induced acute autoimmune hepatitis during combination therapy
with atorvastatin and ezetimibe." van Heyningen C. Ann Clin Biochem.
2005 Sep;42(Pt 5):402-4.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16168199&query_hl=2
"A case is presented of a patient who developed acute hepatitis during
cholesterol-lowering treatment with atorvastatin and ezetimibe.
Further investigations reveal a probable drug-induced autoimmune
hepatitis, and ezetimibe is considered to be the most likely causal
agent. This case is the first report of an autoimmune hepatitis
associated with ezetimibe therapy."
ADDITIONAL BACKGROUND REFERENCE
=================================
"Lipid-lowering: Can ezetimibe help close the treatment gap?" Review.
Ryan C. Neal, Md and Peter H. Jones, MD. CLEVELAND CLINIC JOURNAL OF
MEDICINE VOLUME 70 - NUMBER 9 SEPTEMBER 2003
http://www.ccjm.org/pdffiles/Neal903.pdf
======
I hope I have provided ample information for you to be prepared for
your presentation. If further clarification is necessary, please let
me know. Otherwise - Good Luck!!!!
Sincerely,
umiat
Search Strategy on Google, Google Scholar, PubMED
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