Rosuvastatin CRESTOR

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Rosuvastatin (CRESTOR)

• Modular Slide Bank
• (Version 1 13/03/2003)

CRESTOR is a trade mark of the AstraZeneca Group
of Companies
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Rosuvastatin Slide BankContents

• OVERALL SUMMARY SLIDE
• Section 1 - Pre-clinical Physicochemical
  features of rosuvastatin
• Section 2 - Clinical pharmacology of
  rosuvastatin
• Section 3 - Rosuvastatin effects on the
  atherogenic lipid profile
• Section 4 - Rosuvastatin effects across
  different patient populations
• Section 5 - Rosuvastatin effects in getting
  patients to reach their cholesterol
  guideline goals
• Section 6 - Rosuvastatin in combination with
  other lipid modifying therapies
• Section 7 - Rosuvastatin effects on lipid ratios
  and apolipoproteins
• Section 8 - Pleiotropic effects of rosuvastatin
• Section 9 - Rosuvastatin tolerability profile
• Section 10 - Ongoing clinical trial plans for
  rosuvastatin

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Rosuvastatin Overall summary of the clinical
development programme

• Well defined and targeted pharmacology
• Delivers greatest reduction in LDL-C reported for
  any statin with added advantage of significant
  increases in HDL-C
• Gets more patients to their cholesterol goals 1,
  2, 3
• At low doses, compared to other statins
• With less need for titration upwards
• Consistent efficacy across a wide range of
  patient populations
• Beneficial effects on apoliproteins and lipid
  ratios, compared to other statins
• Well tolerated, and comparable profile to
  currently available statins
• Large, comprehensive and evolving programme of
  further clinical development, demonstrating
  AstraZenecas commitment to rosuvastatin in
  evaluating cardiovascular risk reduction and
  patient outcomes

1 - National Cholesterol Education Program-Adult
Treatment Panel 3rd Report (NCEP ATP-III) 2 -
Joint European Societies (European) 3 - Japanese
Atherosclerosis Society (JAS)
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Section 1

• Pre-clinical physicochemical features of
  rosuvastatin

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Overview Pre-clinical physicochemical features
of rosuvastatin

• A potent inhibitor of HMG-CoA reductase
• X-Ray crystallography Provides a molecular
  rationale for the potent inhibition seen with
  rosuvastatin
• More bonding interactions with HMG-CoA reductase
  than any other statin
• A Pure enantiomer
• A Hydrophilic statin
• Hepatoselective statin
• Targeted site of action
• Undergoes limited metabolism

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Rosuvastatin Mechanism of actionInhibits
HMG-CoA reductase, the rate limiting step of
cholesterol biosynthesis
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RosuvastatinA new hydrophilic statin single
enantiomer
Buckett et al., (2000) McTaggart et al., (2001)
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Rosuvastatin Potent inhibitor of HMG-CoA
reductase in human catalytic domain
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Rosuvastatin Undergoes limited metabolism

• No apparent metabolism of rosuvastatin in human
  microsomes in vitro
• 48 hour incubation of rosuvastatin with human
  hepatocytes shows only a very slow rate of
  metabolism
• Some metabolism by cytochrome P450 2C9 and 2C19
  detected but little or none by 3A4
• Rosuvastatin has a low potential for interaction
  at cytochrome P450 enzymes

McCormick et al., (2000) Martin PD et al., (2000)
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Rosuvastatin X-Ray crystallography provides
molecular rationale for potent enzyme inhibition
The rosuvastatinHMG-CoA reductase complex has
more bonding interactions than any other statin
Istvan and Deisenhofer (2001)
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Rosuvastatin HepatoselectiveCholesterol
synthesis inhibited in hepatocytes at 1000-fold
lower concentrations than fibroblasts
Inhibition of Cholesterol Synthesis in Rat
Hepatocytes and Rat Fibroblasts
Buckett et al., (2000)
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Cerivastatin Non hepatoselective Cholesterol
synthesis inhibited in fibroblasts and
hepatocytes at similar concentrations
Inhibition of Cholesterol Synthesis in Rat
Hepatocytes and Rat Fibroblasts
Buckett et al., (2000)
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Rosuvastatin pravastatin are hepatoselective
Buckett et al., (2000)
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Rosuvastatin High uptake clearance in to liver
Tissue microautoradiography Uptake clearance of
rosuvastatin into rat liver and other tissues
following 5mg/kg 14C rosuvastatin IV
administration
Nezasa et al., (2000)
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Rosuvastatin Well defined pharmacologyA
comparison to other statins
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Section 2

• The clinical pharmacology of rosuvastatin

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Overview How does the clinical pharmacology for
rosuvastatin compare to other statins ?

• Well defined pharmacology
• Low systemic bioavailability ? 20
• Plasma protein binding ? 90, mainly to albumin
• Cmax AUC are approximately linear
• 85-95 of pharmacological activity is unchanged
  rosuvastatin
• Excreted predominantly via faecal route (90)
• Long elimination half-life (?19 hours) consistent
  with once daily dosing
• Limited metabolism in vitro and in vivo
• No significant metabolism through Cytochrome P450
• Low potential for drug interactions
• Effects unaltered by
• Age or Gender
• AM or PM dosing
• Concomitant food intake
• Mild-to-moderate hepatic impairment
• Mild-to moderate renal impairment

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Rosuvastatin Well defined single dose
pharmacokinetics
Plasma rosuvastatin concentration Change from
baseline in 24 subjects
100
10
Rosuvastatin plasma concentration (ng/ml)
1
0
10
20
30
40
50
60
70
80
0.1
Time post dose (hours)
Warwick et al., (2000)
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Rosuvastatin Well defined multiple dose
pharmacokinetics
Plasma rosuvastatin concentration Change from
baseline in 12 subjects following 7 daily oral
doses
Warwick et al., (2000)
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Rosuvastatin Well defined multiple dose
pharmacokineticsPlasma concentration at 24 hours
after dosing
Plasma rosuvastatin concentration Change from
baseline in 12 subjects
Warwick et al., (2000)
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Rosuvastatin Undergoes limited metabolism in
humans

• 90 of rosuvastatin remains non-metabolised and
  is recovered unchanged
• Main metabolites identified are
• N-desmethyl metabolite (active 16-50 of activity
  of parent compound)
• 5S-Lactone metabolite
• Unchanged rousvastatin accounts for gt90 of the
  circulating HMG-CoA reductase inhibitor activity
• 90 of an oral dose is recovered in faeces, 10
  in urine

Olsson et al., (2002) Rosuvastatin Summary of
Product Characteristics
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Rosuvastatin Limited drug-drug interactions

• No clinically significant interactions seen or
  expected with
• Fluconazole / Ketoconazole / Itracnoazole
• Fenofibrate
• Digoxin
• Drugs mediated by cytochrome P450 metabolism
• Interactions with limited clinical significance
• Oral contraceptive pill - ? ethinyl oestradiol
  and norgestrel levels
• Antacid - ? 50 rosuvastatin levels
• Erythromycin - ? 20-30 rosuvastatin plasma
  levels
• Warfarin ? INR
• Interactions resulting in not recommended for
  use
• Gemfibrozil 2x increase in rosuvastatin plasma
  levels
• Interactions resulting in contraindication to
  concomitant use
• Cyclosporin 7x increase in rosuvastatin plasma
  levels

Rosuvastatin Summary of Product
Characteristics Martin PD et al., (2001) Cooper
et al., (2001) Kemp et al., (2001)
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Rosuvastatin Pharmacokinetics unaltered by age
Plasma rosuvastatin concentration Change from
baseline in 32 subjects receiving rosuvastatin
40mg
Martin PD et al., (2002)
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Rosuvastatin Pharmacokinetics unaltered by gender
Plasma rosuvastatin concentration Change from
baseline in 32 subjects receiving rosuvastatin
40mg
Martin PD et al., (2002)
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Rosuvastatin Pharmacokinetics unaltered in
mild-to-moderate hepatic impairment
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Rosuvastatin Degree of LDL-C reductions
unaltered by AM or PM dosing
LDL-C LS mean change from baseline over 14 days
in 21 subjects receiving rosuvastatin 10mg
Martin PD et al., (2002)
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Rosuvastatin Like other statins, increasing
severity of hepatic impairment results in lower
LDL-C reduction
LDL-C LS mean change from baseline at week 2 in
18 subjects receiving rosuvastatin 10mg
Simonson SG et al., (2001)
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Rosuvastatin Low systemic bioavailability
Olsson et al., (2002) Rosuvastatin Summary of
Product Characteristics
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Rosuvastatin Well defined pharmacology

• Summary of Absorption Distribution Metabolism
  Excretion (ADME)
• Orally administered
• Absolute bioavailability of approximately 20
• Plasma protein binding of approximately 90,
  mainly to albumin
• Mean volume of distribution at steady state of
  134L
• Cmax and AUC are approximately linear with dose
• 8595 of circulating active HMG-CoA reductase
  inhibitory activity is unchanged rosuvastatin
• Minimal in vivo metabolism
• No clinically significant interactions with known
  inhibitors of cytochrome P450 (CYP) 3A4
• After oral administration of 14C rosuvastatin,
  90 of radioactivity is recovered in faeces, 10
  in urine
• Elimination T1/2 is approximately 19 h

Warwick et al., (2000) Martin PD et al., ACCP
(2000) Olsson et al., (2002)
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Section 3

• Rosuvastatin effects on the atherogenic lipid
  profile

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Overview How does rosuvastatin monotherapy
affect the atherogenic lipid profile in
hypercholesterolaemic patients compared to
current therapies ?

• LDL
• Clear dose-response for LDL-C lowering
• Both Caucasian and Japanese populations
• Rapid response for LDL-C lowering
• Superior LDL-C lowering vs. other statins at low
  dose
• atorvastatin / simvastatin / pravastatin
• Superior LDL-C lowering response vs. atorvastatin
• HDL-C
• Superior HDL-C raising vs. other statins at low
  dose
• atorvastatin / simvastatin / pravastatin
• HDL-C increases sustained across dose range
• TG
• Comparable TG lowering vs. atorvastatin at low
  dose
• Superior TG lowering vs. other statins at low
  dose
• simvastatin / pravastatin

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Rosuvastatin Clear dose response for LDL-C
lowering in patients with hypercholesterolaemia
LDL-C LS mean change from baseline at week
6 (Dose Ranging Study)
Olsson et al., (2002)
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Rosuvastatin Clear dose response for LDL-C
lowering in Japanese patients with
hypercholesterolaemia
LDL-C LS mean change from baseline at week
6 (Dose Ranging Study)
Saito et al., (2002)
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Rosuvastatin Rapid LDL-C loweringApproximately
90 of effect seen within 2 weeks
LDL-C LS mean change from baseline at week
6 (Dose Ranging Study)
Olsson et al., (2001)
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Rosuvastatin 10mg is superior in lowering LDL-C,
non-HDL-C and raising HDL-C compared to
atorvastatin 10mg in patients with hyperlipidaemia
Lipoprotein profile LS mean change from baseline
at week 12 (Pooled Data)
Blasetto et al., (2003)
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Rosuvastatin 10mg is superior in lowering LDL-C,
non-HDL-C, TG and raising HDL-C compared to
simvastatin 20mg pravastatin 20mg in patients
with hyperlipidaemia
Lipoprotein profile LS mean change from baseline
at week 12 (Pooled Data)
Blasetto et al., (2003)
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Rosuvastatin Superior LDL-C lowering response
compared to atorvastatin in patients with
hyperlipidaemia
LDL-C Linear-regression analysis of mean change
from baseline at week 6
Dose, mg (log scale)
5
40
10
20
80
0
10
rosuvastatin atorvastatin
20
30
Change from baseline ()
40
50
60
70
Adapted from Schneck et al., (2003)
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Rosuvastatin HDL-C raising sustained across dose
range, compared to atorvastatin in patients with
hyperlipidaemia
HDL-C LS mean change from baseline at week 6
Adapted from Schneck et al., (2003)
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Section 4

• Rosuvastatin effects across different patient
  populations

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Overview Are the effects of rosuvastatin
monotherapy on the atherogenic lipid profile
maintained across patient populations ?

• Consistent efficacy on the atherogenic lipid
  profile across patient populations
• Hypertriglyceridemia
• Heterozygous familial hypercholesterolemia
• Japanese patients
• Metabolic syndrome
• Elderly (gt65 years)
• All Women Post-menopausal women
• Hypertensive patients (BPgt140/90 mmHg)
• Type 2 Diabetic patients
• Patients with atherosclerosis
• Obese patients (BMI gt30kg/m2)

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Rosuvastatin Sustained effects on the
atherogenic lipid profile across 10mg to 40mg in
patients with hypertriglyceridemia
Lipoprotein profile LS mean change from baseline
at week 6
Hunninghake et al., (2001)
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Rosuvastatin Similar changes to lipid profile in
patients with / without the metabolic syndrome
Lipoprotein profile LS mean change from baseline
at week 12 with rosuvastatin 10mg
Ballantyne et al., (2003)
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Rosuvastatin Superior LDL-C lowering HDL-C
raising compared to atorvastatin in patients with
heterozygous familial hypercholesterolemia
Lipoprotein profile LS mean change from baseline
at weeks 6-18
Stein et al., (2001)
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Rosuvastatin Sustained effects on the
atherogenic lipid profile across 1mg to 40mg in
Japanese patients with hypercholesterolemia
Lipoprotein profile LS mean change from baseline
at week 6
Saito et al., (2002)
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Rosuvastatin 10mg produces consistent effects on
reducing LDL-C TG and raising HDL-C across a
wide range of patient populations
Lipoprotein profile LS mean change from baseline
at week 12
Blasetto et al., (2003)
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Rosuvastatin 10mg produces consistent effects on
reducing non-HDL-C TC across a wide range of
patient populations
Lipoprotein profile LS mean change from baseline
at week 12
Blasetto et al., (2003)
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Section 5

• Rosuvastatin effects in getting patients to reach
  their cholesterol guideline goals

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Overview How does rosuvastatin compare to other
statins in terms of getting patients to reach
their cholesterol guideline goals ?

• More hypercholesterolaemic patients achieve their
  cholesterol guideline goals compared to other
  statins, at low doses
• NCEP ATP-II III
• Joint European Societies (European)
• Japanese Atherosclerosis Society (JAS)
• Reduced need for hypercholesterolaemic patients
  to be titrated upwards from low doses, to reach
  their cholesterol guideline goals, compared to
  other statins
• NCEP ATP-II
• More heterozygous FH patients achieve their
  cholesterol guideline goals compared to
  atorvastatin
• NCEP ATP-II

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Rosuvastatin 10mg enables more patients with
hypercholesterolemia to reach their NCEP-ATP III
LDL-C goals than atorvastatin 10mg
Patients reaching NCEP ATP-III LDL-C goals by
risk category at week 12 (Pooled Data)
Shepherd et al., (2003)
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Rosuvastatin 10mg enables more patients with
hypercholesterolemia to reach their NCEP-ATP III
LDL-C goals than simvastatin 20mg
Patients reaching NCEP ATP-III LDL-C goals by
risk category at week 12 (Pooled Data)
Shepherd et al., (2003)