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Rosuvastatin
1. New era ofNew era of
Dyslipidaemia treatmentDyslipidaemia treatment
RovirosRoviros (Rosuvastatin)(Rosuvastatin)
Dr Jahanzaib Sheikh
Nabi Qasim Pharma
2. Global Burden of Cardiovascular Disease
According to WHO estimates:
• 16.6 million people die of CVD worldwide
each year
• CVD contributed to approximately one third
of global deaths
In 2001:
• 7.2 million deaths from CHD
• 5.5 million deaths from stroke
Adapted from International Cardiovascular Disease Statistics 2003; American Heart AssociationAdapted from International Cardiovascular Disease Statistics 2003; American Heart Association
3. Risk Factors for Cardiovascular Disease
• Modifiable
– Smoking
– Dyslipidaemia
• raised LDL cholesterol
• low HDL cholesterol
• raised triglycerides
– Raised blood pressure
– Diabetes mellitus
– Obesity
– Dietary factors
– Thrombogenic factors
– Lack of exercise
– Excess alcohol consumption
• Non-modifiable
– Personal history of CHD
– Family history of CHD
– Age
– Gender
4. Levels of Risk Associated with Smoking,
Hypertension and Hypercholesterolaemia
x1.6 x4
x3
x6
x16
x4.5 x9
HypertensionHypertension
(SBP >195 mmHg)(SBP >195 mmHg)
Serum cholesterol levelSerum cholesterol level
(>8.5 mmol/L, 330 mg/dL)(>8.5 mmol/L, 330 mg/dL)
SmokingSmoking
Adapted from Poulter N et al., 1993
5. Cholesterol: A Major Risk Factor
• In the USA, 102 million people have elevated
total cholesterol (>200 mg/dL, 5.2 mmol/L)1
• In EUROASPIRE II, 58% of patients with established
CHD had elevated total cholesterol
(≥5 mmol/L, 190 mg/dL)2
• 10% reduction in total cholesterol results in:
– 15% reduction in CHD mortality (P<0.001)
– 11% reduction in total mortality (P<0.001)3
• LDL-C is the primary target to prevent CHD
Adapted from: 1. American Heart Association. Heart and Stroke Statistical Update; 2002; 2. EUROASPIRE IIAdapted from: 1. American Heart Association. Heart and Stroke Statistical Update; 2002; 2. EUROASPIRE II
Study Group.Study Group. Eur Heart JEur Heart J 2001;2001;2222:554–572; 3. Gould AL:554–572; 3. Gould AL et al. Circulationet al. Circulation 1998;1998;9797:946–952.:946–952.
6. Cholesterol: A Major Risk Factor
• In the USA, 102 million people have elevated
total cholesterol (>200 mg/dL, 5.2 mmol/L)1
• In EUROASPIRE II, 58% of patients with
established CHD had elevated total
cholesterol (≥5 mmol/L, 190 mg/dL)2
Adapted from: 1. American Heart Association. Heart and Stroke Statistical Update; 2002; 2. EUROASPIRE IIAdapted from: 1. American Heart Association. Heart and Stroke Statistical Update; 2002; 2. EUROASPIRE II
Study Group.Study Group. Eur Heart JEur Heart J 2001;2001;2222:554–572; 3. Gould AL:554–572; 3. Gould AL et al. Circulationet al. Circulation 1998;1998;9797:946–952.:946–952.
7. Meta-analysis of 38 primary and secondary prevention trials, with more
than 98,000 patients in total
0 4 8 12 16 20 24 28 32 36
–1.0
–0.8
–0.6
–0.4
–0.2
–0.0
Mortality in coronary heart disease, p=0.012
Total mortality, p=0.04
Lowering of cholesterol (%)
Mortality, log
odds ratio
Benefit of Lowering Cholesterol
Gould AL et al. Circulation 1998;97:946–952
8. Relationship Between Changes in
LDL-C and HDL-C Levels and CHD Risk
Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001.
http://hin.nhlbi.nih.gov/ncep_slds/menu.htm
1% decrease
in LDL-C reduces
CHD risk by
1%
1% increase
in HDL-C reduces
CHD risk by
3%
9. Many Patients in Need of Lipid Lowering
Therapy Remain Untreated –
EUROASPIRE II
39% untreated
Lipid management assessed in 5226 patients with CHD at least 6
months after discharge who qualify for treatment
Euro Heart J 2001;22:554-772
10. Many Patients that are Treated
are Still not Getting to Goal
2989 patients†
1575 (53%) not
at goal on
starting dose
1414 (47%) at
goal on starting
dose
838
(53%) not
titrated
737 (47%)
titrated
478 (65%)
not at goal
†
Patients with and LDL-C goal of <100mg/dL (CHD and/or diabetes mellitus) with
HDL-C ≤45 mg/dL
Simpson RJ Circulation 2001;104:II–829
259 (35%)
at goal
11. Adult Treatment Panel IIIAdult Treatment Panel III
(ATP III) Guidelines(ATP III) Guidelines
National Cholesterol
Education Program
12. LDL Cholesterol Levels andLDL Cholesterol Levels and
CHD Event Rates in Major Statin TrialsCHD Event Rates in Major Statin Trials
311.8351311677LIPS
242.6351509014LIPID
352.0391582102ALERT
360.93913110305ASCOT-LLA
193.8391475804PROSPER
272.33913120536HPS
242.6391404159CARE
371.0§
391506605AFCAPS
321.5501936595WOSCOPS
345.2‡
6619044444S
CHD
risk reduction
(%)
CHD
event
rate/year†
LDL-C net
change
(mg/dL§§
)*
Baseline
LDL
(mg/dL§§
)
Sample
size (n)Study
CHD events refers to cardiac death or nonfatal MI, unless otherwise indicated.
*Placebo-subtracted change from baseline;
†for placebo treated patients;
‡including silent MI plus resuscitated cardiac arrest;
§including unstable angina.
§§1mmole/L LDL = 38.6 mg/dL
14. Update to ATP III Guidelines:Update to ATP III Guidelines:
RationaleRationale
• Since ATP III completion in 2001, 5 large clinical
outcome trials of statin therapy have been
published
– Heart Protection Study (HPS)
– Prospective Study of Pravastatin in the Elderly at Risk
(PROSPER)
– Antihypertensive and Lipid-Lowering Treatment to Prevent Heart
Attack Trial—Lipid-Lowering Trial (ALLHAT-LLT)
– Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm
(ASCOT-LLA)
– Pravastatin or Atorvastatin Evaluation and Infection Therapy
(PROVE-IT) trial
• ATP III update incorporates information from
these trials
Grundy SM et al. Circulation. 2004;110:227-239.
15. NCEP ATP III LDL Cholesterol GoalsNCEP ATP III LDL Cholesterol Goals
CHD <2≥2
LDLcholesterollevel(mg/dL)
Risk factors
70 -
130 -
100 -
160 -
(National Cholesterol Education Program, Adult Treatment Panel III, 2004)
Target
70
mg/dL
Target
100
mg/dL
16. 2004 NCEP-ATP III Guidelines2004 NCEP-ATP III Guidelines
Risk Category LDL Goal
Initiate TLC
(Therapeutic
Lifestyle
Changes)
Consider Drug
Therapy
High risk:
CHD or
CHD Risk Equivalents
<100 mg/dl
(Option:
<70 mg/dl)
≥100 mg/dl
≥130 mg/dl
≥100 mg/dl
(<100 mg/dL: consider drug
options)
2+ Risk
Factors
Moderately high
risk:
10-20% risk <130 mg/dl
(Option: <100
mg/dl)
≥130 mg/dl
≥ 130 mg/dl
(100–129 mg/dL:
consider drug options)
Moderately risk:
<10% risk
≥160 mg/dl
Lower risk:
0-1 Risk Factor
<160 mg/dl ≥160 mg/dl
≥ 190 mg/dl
(160–189 mg/dL:
LDL-C–lowering drug
optional)
×
18. CholestyramineCholestyramine
Mechanism of action
Bind bile acids and metabolites of cholesterol in the
intestine through anion exchange
Pharmacodynamics
Moderate reduction in LDL-C levels
- LDL-lowering potential increases when
combined w/ other agents (e.g. statins)
- May raise TG levels in some p’ts
- ↓ LDL-C by 15-30%
- ↑ HDL-C by 3-5%
Adverse effects
GI distress (constipation, bloating) 、 interfere with
absorption of fat-soluble
vitamins 、 triglyceridemia 、 hyperuricemia
19. FibratesFibrates
Mechanism of action
As ligands for the nuclear transcription receptor, peroxisome
proliferator-activated receptor-apha (PPAR-α). Increase
lipolysis of lipoprotein triglyceride via LPL.
Pharmacodynamics
Lower TG & raises HDL
- Primarily targets atherogenic dyslipidemia including
diabetic dyslipidemia
- ↓ LDL-C by 5-20% (in non-hypertriglyceridemic individuals)
- ↑ HDL-C by 10-35%; ↓ TG by 20-50%
Adverse effects
GI symptoms, headache, drowsiness, dizziness,
myopathy, gallstone rish , arrhythmias
20. Nicotinic AcidNicotinic Acid
Mechanism
Alter lipid levels by inhibiting lipoprotein synthesis &
decreasing the production of VLDL particles by the liver
Pharmacodynamics
Most effective at raising HDL levels of the lipid-
modifying drugs
- ↓ LDL-C by 5-25%
- ↑ HDL-C by 15-35%
- ↓ TG by 20-50%
Adverse effects
Flushing, itching, rash, GI upset
21. EzetimibeEzetimibe
Mechanism
Inhibit absorption of cholesterol from intestine.
Pharmacodynamics
A decreased delivery of cholesterol to the liver.
Reduction of hepatic cholesterol stores.
An increased clearance of cholesterol from the blood.
- ↓ total LDL-C ↓ LDL-C
- ↓ TG ↓ Apo-B
- ↑ HDL-C
Adverse effects
headache, Chest pain, arthralgia, GI distress
22. StatinsStatins
Mechanism
Inhibit HMG CoA reductase which is the rate-limiting step
in cholesterol biosynthesis.
Pharmacodynamics
Most effective class of drugs at lowering LDL-C levels
- ↓ LDL-C by 18-55%
- ↑ HDL-C by 5-15%
- ↓ TG by 7-30%
Adverse reactions
myopathy, rhabdomyolysis, elevations of serum
aminotransferase activity
23. Mechanism of Action of StatinsMechanism of Action of Statins
Cholesterol Synthesis PathwayCholesterol Synthesis Pathway
acetyl CoA
HMG-CoA
mevalonic acid
mevalonate pyrophosphate
isopentenyl pyrophosphate
geranyl pyrophosphate
farnesyl pyrophosphate
squalene
cholesterol
dolicholsubiquinones
HMG-CoA synthase
HMG-CoA reductase
Squalene synthase
StatinsX
25. Only about 50% of patients with high
LDL-C achieve goal on current lipid lowering therapies
– Non-compliance
– Lack of effective treatment
– Fear of high dose titration
More effective cholesterol-lowering
agents are needed to attain LDL-C goals1,2
1
Kotseva, K, Wood D, de Backer, G et al. 2001
2
Pearson T et al. 2000
Why Do We Need a New Statin?Why Do We Need a New Statin?
26. Wish List of Features of New StatinWish List of Features of New Statin
High efficacy at start dose
Potent HMG-CoA inhibition
Lowers LDL, VLDL, Lp(a), remnants
Raises HDL
Anti-inflammatory, anti-thrombotic
Good safety profile
Selective for target organ – liver
Minimal potential for drug interactions
Useful in a wide range of patients
Cost effective
After Hanefeld, Int J Clin Pract 2001 55;399–405
27. Statin PharmacophoreStatin Pharmacophore
OO
N
N
S
N
OH
OH
O
O
CH3
CH3
CH3
F
CH3
Ca(3R, 5S)
Relative lipophilicityRelative lipophilicity **
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
rosuvastatin
cerivastatin
simvastatin
fluvastatin
atorvastatin
pravastatin
** log D at pH 7.4
Buckett et al., (2000); Mc
RosuvastatinRosuvastatin::
A newA new hydrophilichydrophilic statin –statin – single enantiomersingle enantiomer
28. Inhibition of Cholesterol Synthesis in Rat Hepatocytes and Rat Fibroblasts
Buckett et al., (2000)
Rosuvastatin:Rosuvastatin: HepatoselectiveHepatoselective
Cholesterol synthesis inhibited in hepatocytes atCholesterol synthesis inhibited in hepatocytes at
1000-fold1000-fold lower concentrations than fibroblastslower concentrations than fibroblasts
0
20
40
60
80
100
120
140
0.1 1 10 100 1000 10000 1000000
% of Control
Mean
Concentration (nM)
Fibroblasts IC50= 331 nM
Hepatocytes IC50= 0.2 nM
29. Cerivastatin: Non hepatoselectiveCerivastatin: Non hepatoselective
Cholesterol synthesis inhibited in fibroblastsCholesterol synthesis inhibited in fibroblasts
and hepatocytes at similar concentrationsand hepatocytes at similar concentrations
Buckett et al., (2000)
100 1000 10000
% of Control
0 0.01 0.1 1 10 100000
0
20
40
60
80
100
120
140
Concentration (nM)
Mean
Fibroblasts IC50= 1.3 nM
Hepatocytes IC50= 2.4 nM
Inhibition of Cholesterol Synthesis in Rat Hepatocytes and Rat Fibroblasts
30. binding interaction
Arg568
and sulphone
Istvan and Deisenhofer (2001)
Rosuvastatin:Rosuvastatin: X-Ray crystallography providesX-Ray crystallography provides
molecular rationale for potent enzyme inhibitionmolecular rationale for potent enzyme inhibition
The rosuvastatin:
HMG-CoA reductase
complex has more
bonding interactions
than any other statin
31. *P<0.05 vs Rosuvastatin; ***P<0.001 vs Rosuvastatin
Rosuvastatin:Rosuvastatin: Potent inhibitor ofPotent inhibitor of
HMG-CoA reductase in human catalytic domainHMG-CoA reductase in human catalytic domain
Three determinations, IC
50
(nM) with 95% confidence limits
Rosuva
5.4
100
10
Ceriva *
10.0
Atorva
8.2
Fluva ***
27.6
Simva *
11.2
Prava
***
44.1
IC50
(nM)
(log scale)
McTaggart et al., (2001)
32. Rosuvastatin:Rosuvastatin:
Well defined pharmacologyWell defined pharmacology
Potency on
enzyme
IC50 (nM)
Cell selectivity
log ratio
Hepatic
Metabolism
by Cyt P450
3A4
Elimination
Half Life
(hours)
rosuvastatin
pravastatin
5.4
44.1
3.3
3.3 1–2
cerivastatin 10.0 –0.14 Yes 2–3
atorvastatin 8.2 2.2 Yes 14
fluvastatin 27.6 –0.04 No 1–2
simvastatin 11.2 0.54 Yes 1–2
≈19No
No
Adapted from Davidson., (2002)
33. PharmacologicPharmacologic properties of Statins
Property Rosuva Atorva Fluva Lova Prava Simva
Prodrug No No No Yes No Yes
Salt form Ca Ca Na None Na None
Single
isormer
Yes Yes Yes Yes Yes Yes
Lipophilicity
(log P)
-0.3 +4.1 +3.2 +4.3 -0.2 +4.7
IC50(nm)
Potency
5 8 28 NA NA 11
Thomas N. Riley, PhD & Jack DeRuiter, PhD (2004)
37. GALAXYGALAXY
AURORA
CORONA
JUPITER
ORION (MRI)
METEOR
ASTEROID (IVUS)
STELLAR
MERCURY I/II
ORBITAL
DISCOVERY
COMETS
LUNAR
PLUTO
POLARIS
PULSAR
ECLIPSE
EXPLORER
PLANET
GALAXY Programme studies with CRESTOR, investigating:
Atherogenic lipid profile
+/- inflammatory markers Atherosclerosis
Reduction in CV
morbidity & mortality
FFPC meeting October 2003: Dr Dave Kallend
38. LSmean%changefrombaseline
-60
-50
-40
-30
-20
-10
0
10 20 40 80
Dose (mg)
CRESTOR atorvastatin simvastatin pravastatin
Log scale
45.8%
55.0%
36.8%
51.1%
28.3%
45.8%
29.7%
20.1%
RosuvastatinRosuvastatin
the most effective statin at lowering LDL- C
STELLAR Study. Am J Cardiol 2003; 92: 152–60.
39. Rosuva
Atorva
Simva
Prava
10 20 40 80
Fluva
Statin Dose Required to AchieveStatin Dose Required to Achieve
45–50%45–50% LDL-C ReductionLDL-C Reduction
mg
Not achieved with max.
authorised dose
Not achieved with max.
authorised dose
Adapted from Jones P.H. 2003
40. RosuvastatinRosuvastatin versus Comparators:versus Comparators:
LDL-C efficacy at 10mg DoseLDL-C efficacy at 10mg Dose
Change in LDL-C from baseline (%)
0 –10 –20 –30 –40 –50 –60
10
mg
*
–5 –15 –25 –35 –45 –55
20
mg
†
40
mg
‡
10
mg
20
mg
80
mg
10
mg
20
mg
40
mg
80
mg
10
mg
20
mg
40
mg Rosuvastatin 10 mg (–46%)
Rosuvastatin
Atorvastatin
Simvastatin
Pravastatin
40
mg
*p<0.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg
†p<0.002 vs atorvastatin 20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg
‡p<0.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg
Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160 The STELLAR StudyThe STELLAR Study
41. Percentage of patients at LDL-C goal at week 61, 2
60%
20%
100%
80%
40%
atorvastatin
10 mg
n=
158
10 mg
20 mg
10 mg
20 mg
simvastatin pravastatin
n=
158
80 mg
40 mg
80 mg
20 mg
40 mg
40 mg
n=160
CRESTOR
10 mg
n=
156
*
P-values
***p<0.002
CRESTOR 10 mg
vs. atorvastatin
10 mg pravastatin
10, 20 & 49 mg and
simvastatin 10, 20,
& 40 mg
10 mg10 mg
20 mg20 mg
10 mg10 mg
20 mg20 mg
Usual start dosesUsual start doses
10%
30%
50%
70%
90%
%patientsreachingLDL-Cgoal*
Rosuvastatin:Rosuvastatin:
10 mg gets more patients to their LDL-C goal
than the start doses of the most commonly used
statins1,2,3,4
References: 1. STELLAR 2. Schuster MERCURY I Am Heart J 2004; 147: 705-12. 3.
Krithiades Eur Heart J Suppl 2004; 6(suppl A): A12-A18.4. Shepherd Am J Cardiol
2003; 92(suppl): 11C-19C. *2003 European goals
43. **P<0.01 vs atorvastatin; ***P<0.001 vs atorvastatin
Rosuvastatin: 10mg enables more patients withRosuvastatin: 10mg enables more patients with
hypercholesterolemia to reach their Joint Europeanhypercholesterolemia to reach their Joint European
Societies LDL-C goals, than atorvastatin 10mgSocieties LDL-C goals, than atorvastatin 10mg
*** ***
**
82
85
81
51
49
64
0
20
40
60
80
100
10-yr CHD risk < 20% High CHD risk All Categories
Joint European Societies Cholesterol Categories
Patientsachievinggoal(%)
rosuvastatin 10mg
atorvastatin 10mg
n=314 n=327n=75 n=66 n=389 n=393
Patients reaching European LDL-C goals by risk category at week 12Patients reaching European LDL-C goals by risk category at week 12
(Pooled Data)(Pooled Data)
Shepherd et al., (2003)
44. 0
10
20
30
40
50
60
70
80
90
100
R10 A10 A20 S20 P40
Patients
at goal
(%)
*
*
*84
*p<0.0001 (R10 vs A10, S20 & P40) 1998 European goal <3.0 mmol/l (116 mg/dl)
88
76
69
62
RosuvastatinRosuvastatin 10 mg10 mg gets more patients to
European LDL-C GoalsEuropean LDL-C Goals
MERCURY I study; Am Heart J 2004; 147: 705-12
45. RosuvastatinRosuvastatin 10 mg10 mg
Patients (%) achieving European LDL-C goalPatients (%) achieving European LDL-C goal
vs A10/A10;
vs A20/A20;
10 vs S20/S20 and P40/R10 vs P40/P40)
al <3.0 mmol/l (116 mg/dl)
MERCURY I study; Am Heart
A10 A10 A20 A20 A20 S20 S20 P40 P40
R10 A10 R10 R20 A20 R10 S20 R10 P40
Patients
at goal
(%)
†
0
10
20
30
40
50
60
70
80
90
100
88
80
86 86 86 8890
84
72
66
* ‡ ‡
Dose (mg)
49. Pleiotropic EffectsPleiotropic Effects ofof RosuvastatinRosuvastatin
in Animal Models of Vascular Diseasein Animal Models of Vascular Disease
↑ eNOS, NO availability
↓ leukocyte-endothelial interactions
↓ superoxide, oxidative stress
Preservation of vascular function in
hypertension and insulin-resistance
Protection against ischaemia-reperfusion
injury
Protection of kidney function and inhibition
of renal fibrosis and glomerulosclerosis
50. StatinsStatins –– Therapeutic RatioTherapeutic Ratio
Therapeutic
Effects
Adverse Effects
Cardiovascular
protection
Muscle
Liver
Drug interactions
Benefit
Risk
51. RosuvastatinRosuvastatin Tolerability and Safety –Tolerability and Safety –
Withdrawals due toWithdrawals due to Adverse EventsAdverse Events
Brewer HB. Am J Cardiol 2003;92(Suppl):23K-29K
Percentage of patients with an adverse event
leading to withdrawal
10
0
2
4
6
8
rosuvastatin simvastatin pravastatin
Percentageofpatients
1
3
5
7
9
2.9%
2.5% 2.5%
(n=3074) (n=1457) (n=1278)
3.2%
atorvastatin
(n=2899)
10-40 mg10-80 mg
10-80 mg
10-40 mg
52. RosuvastatinRosuvastatin Tolerability and SafetyTolerability and Safety
- Muscle Effects- Muscle Effects
As with other statins, effects on skeletal muscle, e.g.
uncomplicated myalgia, myopathy and, rarely,
rhabdomyolysis have been reported in patients treated
with rosuvastatin
Incidence of treatment-related myopathy*
in clinical
trials was low in patients treated with rosuvastatin up to
40 mg (<0.1%) which is similar to that seen with other
currently marketed statins1
Frequency of rhabdomyolysis with rosuvastatin is very
rare (<0.01%) which is in line with that reported for
other marketed statins2
*defined as CK >10 ULN plus muscle symptoms
1. Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K
2. Data on File
Please refer to local Prescribing Information
53. RosuvastatinRosuvastatin - Muscle Effects- Muscle Effects
CK >10CK >10 xx ULN: Frequency byULN: Frequency by
LDL-C ReductionLDL-C Reduction
Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K
Cerivastatin (0.2–0.8 mg)
Rosuvastatin (10–40 mg)
Pravastatin (40–80 mg)
Atorvastatin (10–80 mg)
Simvastatin (40–80 mg)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
20 30 40 50 60 70
LDL-C reduction (%)
CK>10×ULN(%)
54. Reported Cases ofReported Cases of Fatal RhabdomyolysisFatal Rhabdomyolysis andand
Numbers for All Statins Dispensed in the US SinceNumbers for All Statins Dispensed in the US Since
These Products Were LaunchedThese Products Were Launched
Variable
Lovastatin Pravastatin Simvastatin Fluvastatin Atorvastatin Cerivasta
tin
Rosuvastati
n
*
Date approved 8/87 10/91 12/91 12/93 12/96 6/97 11/02#
Fatal cases of
rhabdomyolysis
19 3 14 0 6 31 0
No. of
prescriptions
dispensed since
marketing began
(in thousands)
99,197 81,364 116,145 37,392 140,360 9,815 10,100
Reporting rate
(per 1 million
prescriptions)
0.19 0.04 0.12 0 0.04 3.16 0
Adapted from: Steffa JA, et al. N Engl J Med. 2002;346:539-540.
*worldwide prescriptions*worldwide prescriptions
#Netherlands (MR ref state)#Netherlands (MR ref state)
55. RosuvastatinRosuvastatin Tolerability and SafetyTolerability and Safety
- Liver Effects- Liver Effects
Elevations in liver transaminase levels are an infrequent
but recognized complication of treatment with statins
Incidence of clinically significant increases in serum
transaminases* with rosuvastatin 10–40 mg in clinical
trials was low (0.2%) which is similar to that seen with
other currently marketed statins1,2
As with other statins:
– liver function tests recommended
– caution in patients who consume excessive quantities of
alcohol and/or have a history of liver disease
– contraindicated in patients with active liver disease
*ALT >3 x ULN on 2 successive occasions
1. Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K
2. Shepherd J et al. Am J Cardiol 2004;94:882-888
Please refer to local Prescribing Information
56. RosuvastatinRosuvastatin – Liver Effects– Liver Effects
Persistent ALT >3Persistent ALT >3 ×× ULN: Frequency byULN: Frequency by
LDL-C ReductionLDL-C Reduction
Persistent elevation is elevation to >3 x ULN on 2 successive occasions
Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K
0.0
0.5
1.0
1.5
2.0
2.5
3.0
20 30 40 50 60 70
LDL-C reduction (%)
PersistentALT>3×ULN(%)
Fluvastatin (20–80 mg)
Rosuvastatin (10–40 mg)
Lovastatin (20–80 mg)
Atorvastatin (10–80 mg)
Simvastatin (40–80 mg)
57. Potential Drug InteractionsPotential Drug Interactions
3A4
Simvastatin
Atorvastatin
Lovastatin
Diltiazem
Clopidogrel
Amiodarone
Cimetidine
Ery/clarithromycin
Ketoconazole
Carbamazepine
St John’s wort
Grapefruit juice
2C92C9
• FluvastatinFluvastatin
• PhenytoinPhenytoin
• FluconazoleFluconazole
• WarfarinWarfarin
• RosuvastatinRosuvastatin
Low potential for
cytochrome P450
interactions with
rosuvastatin
58. Rosuvastatin SafetyRosuvastatin Safety
Safety profile of rosuvastatin, includingSafety profile of rosuvastatin, including
effects on liver enzymes and creatineeffects on liver enzymes and creatine
kinase, compares favorably to those ofkinase, compares favorably to those of
other marketed statins from 10–40 mgother marketed statins from 10–40 mg
daily in all pre-approval studiesdaily in all pre-approval studies
• Hydrophilic propertiesHydrophilic properties
• Good selectivity for target organ – liverGood selectivity for target organ – liver
• Limited metabolism by cytochrome P450Limited metabolism by cytochrome P450
((2C92C9‚‚2C192C19))
59. RosuvastatinRosuvastatin:: DDrugrug InteractionsInteractions
Interactions of limited significance:Interactions of limited significance:
• Oral contraceptives -Oral contraceptives - ↑↑ethinyl oestradiol and norgestrelethinyl oestradiol and norgestrel
• Antacid -Antacid - ↓↓50% rosuvastatin levels50% rosuvastatin levels
• Erythromycin -Erythromycin - ↓↓20–30% rosuvastatin plasma levels20–30% rosuvastatin plasma levels
• Warfarin – transientWarfarin – transient ↑↑INR in some patientsINR in some patients
Not recommended for use with:Not recommended for use with:
• Gemfibrozil – 2x increase inGemfibrozil – 2x increase in rosuvastatinrosuvastatin plasma levelsplasma levels
(Note: Fenofibrate may be co-administered)(Note: Fenofibrate may be co-administered)
Contraindication:Contraindication:
• Cyclosporin – 7x increase in rosuvastatin AUCCyclosporin – 7x increase in rosuvastatin AUC
• ANY fibrate with rosuvastatin 40 mgANY fibrate with rosuvastatin 40 mg
60. 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)
Rosuvastatin: Limited drug-drug interactionsRosuvastatin: Limited drug-drug interactions
61. RosuvastatinRosuvastatin has Extensive Clinical and
post-Market Experience Mar 2005
• Approved in 73 countries world-wide
• Over 5 million patients treated
• Over 20 million prescriptions written
• Over 45,000 patients have been treated with
RosuvastatinRosuvastatin in our clinical trial programme
---- GALAXY program
According to WHO estimates, 16.6 million people around the globe die of CVD each year, contributing to nearly one third of global deaths.1-3 In 2001 there were 7.2 million deaths from heart disease and 5.5 million from stroke.1-3 Another 15 million each year survive minor strokes and 600 million people with high blood pressure are at risk of heart attack, stroke and cardiac failure.1-3
Not only is CVD costly in terms of clinical care but it affects individuals in their peak mid-life years, disrupting the future of families dependent on them and undermining the economic basis of countries by reducing the productivity of the workforce.
References
1. International Cardiovascular Disease Statistics 2003; American Heart Association.
2. The World Health Report, 2002.
3. Cardiovascular Diseases — Prevention and Control. WHO CVD Strategy, 2001/2002.
Some of the risk factors that predispose an individual to the development or progression of CHD are outlined above. Evidence has shown that lifestyles associated with a ‘western’ culture such as a diet rich in saturated fats and high in calories, smoking and physical inactivity, are some of the modifiable risk factors leading to an increase in the prevalence of CHD. Of these, three are considered to be of prime importance:
Smoking is responsible for 50% of all avoidable deaths, of which half are due to CVD.
Raised blood pressure has been found to be an important risk factor for the development of CHD, cardiac failure and cerebrovascular disease. The greater the increase in blood pressure, the higher the risk. Greatest benefit of blood pressure lowering is seen in those at higher risk. Even modest reductions produce substantial benefits in those with multiple risk factors.
Dyslipidaemia, in particular, raised low-density lipoprotein (LDL) cholesterol and triglyceride levels, and low high-density lipoprotein (HDL) cholesterol are associated with increased risk of CHD. Since 60–70% of plasma cholesterol is transported in the LDL fraction, total cholesterol measurement has been widely used in epidemiological studies rather than plasma LDL cholesterol.
Reference
Pyörälä K et al. Eur Heart J 1994; 15: 1300–1331.
Multiple risk factors for CHD are usually present in an individual; rarely do they occur in isolation. When risk factors co-exist the effect is often compounded and their combined effect is greater than the sum of their individual effects.1
Multiple risk factors are also associated with the Metabolic Syndrome which is characterised by dyslipidaemia, hypertension, insulin resistance, visceral distribution of body fat, and a prothrombotic state.2
References
1. Poulter N. In Cardiovascular Disease: Risk Factors and Intervention. Eds: Poulter N, Sever P, Thom S. Radcliffe Medical Press, Oxford, 1993.
2. Deedwania PC. Am J Med 1998;105(1A);1S–3S.
It has been estimated that in the USA approximately 102 million people have elevated total cholesterol levels of &gt;200 mg/dL (5.2 mmol/L) and 41 million have levels of &gt;240 mg/dL (6.2 mmol/L).1 In EUROASPIRE II, 58% (n=5556) of patients with established CHD were found to have elevated cholesterol levels (5 mmol/L, 190 mg/dL).2
Early trials have shown that a reduction in total cholesterol results in a reduction in the incidence of CHD events. In addition, a meta-analysis of 38 trials3 has shown that for every 10% reduction in total cholesterol, CHD mortality is reduced by 15%, and total mortality by 11% (both P&lt;0.001). Similar reductions were seen with all lipid-modifying treatments studied. Thus, total cholesterol is a modifiable risk factor for CHD and total mortality.4
Low-density lipoprotein (LDL) cholesterol has been recognised as a prime target for lipid intervention to prevent CHD. Under NCEP ATP III LDL-C guidelines it has been estimated that approximately 36 million patients would be suitable for drug therapy.5 The intensity of intervention depends not only on raised cholesterol or LDL-C but also on the presence of a number of other risk factors for CHD.
References
1. American Heart Association. Heart and Stroke Statistical Update; 2002.
2. EUROASPIRE II Study Group. Eur Heart J 2001;22:554–572.
3. Gould AL et al. Circulation 1998;97:946–952.
4. National Cholesterol Education Program. Circulation 1994;98(3):1333–1445.
5. Fedder DO, Koro CE, L’Italien GJ. Circulation 2002;105:152–156.
It has been estimated that in the USA approximately 102 million people have elevated total cholesterol levels of &gt;200 mg/dL (5.2 mmol/L) and 41 million have levels of &gt;240 mg/dL (6.2 mmol/L).1 In EUROASPIRE II, 58% (n=5556) of patients with established CHD were found to have elevated cholesterol levels (5 mmol/L, 190 mg/dL).2
Early trials have shown that a reduction in total cholesterol results in a reduction in the incidence of CHD events. In addition, a meta-analysis of 38 trials3 has shown that for every 10% reduction in total cholesterol, CHD mortality is reduced by 15%, and total mortality by 11% (both P&lt;0.001). Similar reductions were seen with all lipid-modifying treatments studied. Thus, total cholesterol is a modifiable risk factor for CHD and total mortality.4
Low-density lipoprotein (LDL) cholesterol has been recognised as a prime target for lipid intervention to prevent CHD. Under NCEP ATP III LDL-C guidelines it has been estimated that approximately 36 million patients would be suitable for drug therapy.5 The intensity of intervention depends not only on raised cholesterol or LDL-C but also on the presence of a number of other risk factors for CHD.
References
1. American Heart Association. Heart and Stroke Statistical Update; 2002.
2. EUROASPIRE II Study Group. Eur Heart J 2001;22:554–572.
3. Gould AL et al. Circulation 1998;97:946–952.
4. National Cholesterol Education Program. Circulation 1994;98(3):1333–1445.
5. Fedder DO, Koro CE, L’Italien GJ. Circulation 2002;105:152–156.
Large-scale intervention trials have shown a clear relationship between reduction of cholesterol (by any means) and reduction in both mortality, due to coronary heart disease, and total mortality. This kind of data has driven guideline bodies to more aggressive recommendations for treatment.
In the USA, the NCEP Expert Panel have estimated, based on data from epidemiology studies as well as intervention studies, that each 1% decrease in LDL-C equates to a 1% reduction in CHD risk.
In addition, every 1% increase in HDL-C equates to a 3% reduction in CHD risk.
Reference
1. Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm
Despite the universally accepted evidence that confirms the benefit of lipid lowering therapy, large observational studies such as EUROASPIRE II have shown that many patients in need of lipid lowering therapy remain untreated. The EUROASPIRE II study was a large survey of lifestyle, risk factor management and drug therapy in over 8000 CHD patients in 15 countries across Europe. The results provide valuable insight into what is actually happening in practice and highlight that Many Patients in need of lipid lowering Therapy Remain Untreated.
Reference:
Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries. Principal results from EUROASPIRE II Euro Heart Survey Programme. Euro Heart J 2001;22:554-772
Even when patients are treated, many are still not getting to goal. This study by Simpson et al which was conducted in approximately 3000 high-risk patients with an LDL-C goal of &lt;100mg/dL, showed that despite the availability of a more effective statin such as atorvastatin, less than half of the population reached treatment goals with the starting dose of a statin. Of those 53% not reaching goals, more than half were never up-titrated. Of the 737 patients who were up-titrated, two thirds never reached treatment goals despite the up-titration.
It can be concluded therefore that:
Too many patients are not achieving their treatment goal at start dose
Too many patients who do not achieve their treatment goal at start dose are not being titrated
Even when patients are titrated, not enough are achieving their treatment goal
These results are supported by those from the EUROASPIRE II study which showed that overall, only approximately half of patients (51%) achieved their cholesterol treatment goal.
Reference:
1. Simpson RJ. Circulation 2001;104:II–829
mmol/L LDL /0.0259 = mg/dL LDL
This slide shows the relationship between LDL-C levels and CV event rate in a number of large statin clinical trials and demonstrates that the lower the level of LDL-C observed, the lower the CV event rate. This observation supports the NCEP recommendations to treat to a target LDL-C concentration.
However, although substantial reductions in LDL-C were obtained with statins (by 23–37%) they do not entirely eliminate events, suggesting that lipid parameters besides LDL-C, such as HDL-C, triglyceride, lipoprotein (a), and LDL particle size and susceptibility to oxidation as well as other risk factors and pleiotropic effects of these drugs, influence CHD risk. The results from on-going trials should answer questions of whether further reductions in LDL-C will provide additional benefit.1
Reference
1. Adapted from Ballantyne CM. Am J Cardiol 1998;82:3Q–12Q.
This slide provides a graphic representation of the NCEP ATP III LDL cholesterol goals. The goal of therapy in patients with CHD is to reduce LDL cholesterol to 100 mg/dL or lower. Patients with established CHD or other atherosclerotic disease should receive drug therapy when LDL cholesterol levels are 130 mg/dL. The degree of risk should indicate the severity of intervention. For example, NCEP guidelines state that for patients without a history of CHD but who have two or more risk factors (such as smoking and hypertension), LDL should be brought below 130 mg/dL. Less aggressive intervention may be warranted if fewer risk factors are present. The LDL cholesterol cut-off is 160 mg/dL for patients with fewer than two risk factors.
Reference
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001; 285: 2486–2497.
Statins, or HMG-CoA reductase inhibitors, are the most recently introduced class of lipid-lowering therapies and the most widely prescribed. The first commercially available statin, derived from the fungus Aspergillus terreus, was lovastatin.1 Pravastatin, also fermentation-derived, was then developed and is structurally related to lovastatin.2 Simvastatin, which is a chemically-modified lovastatin at a single position, has been used widely since 1991. The first synthetic or second generation statin was fluvastatin, available in the USA in 1994.
The body obtains cholesterol and triglyceride either by synthesising them in the liver or from the diet or storage sites in adipose tissue. The cholesterol synthesis pathway is a complex process involving many biochemical pathways and feedback mechanisms in the liver. Statins inhibit the HMG-CoA reductase, the enzyme involved in the rate-limiting step in the formation of cholesterol, which is usually responsible for two-thirds of the body’s cholesterol.3 In response to this the hepatocytes up-regulate and increase the number of LDL receptors, increasing binding and removal of LDL cholesterol and LDL precursors from the plasma. This results in an increase in HDL levels although the mechanism involved has not been fully established.4
synthesis of cholesterol in the liver accounts for some 60–70% of the total cholesterol pool
References
1. Endo A. J Lipid Res 1992;33:1569–82.
2. Stein EA. Atherosclerosis 1994;108:S105–16.
3. Blumenthal RS. Am Heart J 2000;139:577-83.
4. Nawrocki JW et al. Atheroscler Thromb Vasc Biol 1995;15:678–82.
Presented:Poster at at the XIIth International Symposium on Atherosclerosis (ISA), Stockholm, June 25-29th 2000.
Citation:Atherosclerosis 2000;151:41 abs MoP29:W6
Am J Cardiol 2001;87(suppl):28B–32B
Background: There is a wide variability in the lipophilicity of available statins and it has been hypothesised that this may be a contributing factor to the ability of statins to act in cells outside of the goal organ (liver) such as muscle.
Study Design:
Aim:To measure the lipophilicity (logD) of rosuvastatin and other statins
Population:In vitro
Numbers:
Methodology:LogD of the statins between 0.01M phosphate buffer, pH 7.4 and octanol (1:100 v/v) was determined using a micro-shake flask method with drug concentration determined by HPLC.
rosuvastatin is a single enantiomer (3R, 5S) formulated and administered as the calcium salt of the active hydroxy acid.
Key Results:
rosuvastatin is relatively hydrophilic statin, intermediate between pravastatin and the other statins.
Conclusions:
rosuvastatin, like pravastatin, is less likely to cross cellular membranes compared to lipophilic statins. This may contribute in part, to the degree of selectivity of effect on cholesterol synthesis between hepatic and non-hepatic cells.
Presented:Poster at the XIIth International Symposium on Atherosclerosis (ISA), Stockholm, June 25-29th 2000.
Citation:Atherosclerosis 2000;151:41 abs MoP29:W6
Background: The primary mechanism of action of a statin is via inhibition of the HMG-CoA (HMG-CoA) reductase enzyme, within the hepatocyte. The more potent the inhibition, the more effective the likely clinical effect on plasma cholesterol reduction. A desirable property in terms of cholesterol inhibition is to targethepatocytes and minimise potential unwanted effects in non-hepatocytes that may arise through this non-hepatic cholesterol inhibition
Study Design:
Aim:To compare rosuvastatin with 5 other statins as to the degree of selectivity of effect between primary rat hepatocytes, rat fibroblasts. Only rosuvastatin data shown here. (Other statin comparisons shown later in slide bank).
Methodology:Comparisons with atorvastatin, simvastatin, cerviastatin, fluvastatin and pravastatin.
Key Results:
Only rosuvastatin data shown here.
Rosuvastatin is much more selective for effects in hepatocytes compared to rat fibroblasts and than atorvastatin, simvastatin, cerviastatin and fluvastatin. (Other statin comparisons shown later in slide bank).
Conclusions:
Rosuvastatin is more selective for effects in hepatocytes compared to rat fibroblasts.
Therefore, from this model, a given dose sufficient to inhibit cholesterol synthesis in liver cells would be 1000x less able to inhibit cholesterol synthesis in non-liver cells, a desirable property that focuses the activity of rosuvastatin on the intended goal organ of the liver.
Presented:Poster at the XIIth International Symposium on Atherosclerosis (ISA), Stockholm, June 25-29th 2000.
Citation:Atherosclerosis 2000;151:41 abs MoP29:W6
Background: The primary mechanism of action of a statin is via inhibition of the HMG-CoA (HMG-CoA) reductase enzyme, within the hepatocyte. The more potent the inhibition, the more effective the likely clinical effect on plasma cholesterol reduction. A desirable property in terms of cholesterol inhibition is to target hepatocytes and minimise potential unwanted effects in non-hepatocytes that may arise through this non-hepatic cholesterol inhibition.
Study Design:
Aim:To compare rosuvastatin with 5 other statins as to the degree of selectivity of effect between primary rat hepatocytes, rat fibroblasts. Only cerivastatin data shown here (Other statin comparisons shown later in slide bank).
Methodology:Comparisons with atorvastatin, simvastatin, cerviastatin, fluvastatin and pravastatin.
Key Results:
Only cerivastatin data shown here.
Cerivastatin is non-selective for effects in hepatocytes compared to rat fibroblasts and similar to simvastatin. (Other statin comparisons shown later in slide bank).
Conclusions:
Cerivastatin is similarly selective for effects in hepatocytes and rat fibroblasts.
The amount of cerivastatin required to have an effect on inhibiting cholesterol synthesis effect in hepatocytes (Liver - target organ for statins in the clinical setting) compared to non-liver, is approximately the same (c.f. Rosuvastatin requires 1000x higher concentrations of drug to inhibit cholesterol synthesis in non-liver fibroblasts, compared to hepatocytes)
Therefore, from this model, a dose of cerivastatin given would inhibit cholesterol synthesis in non-liver cells as well as hepatocytes, highlighting the non-selective nature of cerivastatin.
Citation:Science 2001; 292: 1160-1164
Background:HMG-CoA reductase (HMGR) catalyses the rate-limiting step in cholesterol biosynthesis. Statins are HMGR inhibitors with inhibition constant values in the nanomolar range that effectively lower serum cholesterol levels and are widely prescribed in the treatment of hypercholesterolaemia.
Study Design:
Aim:To determine how statins prevent the binding of HMGR, by examining the structures of the catalytic portion of human HMGR complexed with six different statins.
Methodology:Determination of six crystal structure of the catalytic portion of human HMGR bound to six different statin inhibitors at resolution limits of 2.3 Å (angstroms) or higher, through X-ray crystallography.
Key Results:
The statins occupy a portion of the binding site of HMG-CoA, thus blocking access of this substrate to the active site. A comparison between the six complex structures illustrates subtle differences in their modes of binding.
Rosuvastatin has the greatest number of bonding interactions with HMGR. In addition to numerous contacts present in other statin-HMGR complex structures, a polar interaction between the Arg 568 side chain and the electronegative sulfone group is unique to rosuvastatin.
Present only in atorvastatin and rosuvastatin are hydrogen bonds between Ser 565 and either a carbonyl oxygen atom (atorvastatin) or a sulfone oxygen atom (rosuvastatin).
The tight binding of statins, and rosuvastatin in particular, is probably due to the large number of van der Waals interactions between inhibitors and with HMGR.
Conclusions:
Rosuvastatin binds tightly to HMGR and has the greatest number of bonding interactions of all statins tested.
Presented:Sponsored Symposium at the XIIth International Symposium on Atherosclerosis (ISA), Stockholm, June 25-29th 2000
Citation:Am J Cardiol 2001;87(suppl):28B–32B
Background:The primary mechanism of action of a statin is via inhibition of the HMG-CoA reductase enzyme, within the hepatocyte. The more potent the inhibition, the more effective the likely clinical effect on plasma cholesterol reduction.
Study Design:
Aim:To determine the activity of rosuvastatin in inhibiting HMG-CoA reductase in a cloned and purified catalytic fragment of the human enzyme.
Population:In vitro
Numbers:3 replicate experiments
Methodology:Cloned and purified human HMG-CoA reductase fragment 419–888, 100µM HMG CoA, 250µM NADPH, incubated with rosuvastatin.
Key Results:
Studies in the purified human catalytic domain showed that rosuvastatin was a highly potent statin (50% inhibitory concentration [IC50 ] of 5.4 nM).
Although the study was not designed to show specific differences between rosuvastatin and other statins (only 3 replicates were performed), the data showed that rosuvastatin was more potent than all the other statins in this model, except for atorvastatin, where a numerical but no statistical difference was shown.
Rosuvastatin potency was 8 times greater than that of pravastatin, the other hydrophilic agent.
Conclusions:
Rosuvastatin is a potent inhibitor of HMG-CoA in a cloned and purified catalytic fragment of the human enzyme. These results are consistent with data from experiments with rat hepatocytes1, rat hepatic microsomes and in vivo assessment of inhibition of rat hepatic cholesterol synthesis2.
References
1. Buckett L, et al. Atherosclerosis 2000;151(1):41 abs MoP29:W6.
2. Smith G, et al. Atherosclerosis 2000;151(1):39 abs MoP29:W6.
Presented: Sponsored Symposium at the International Symposium on Atherosclerosis (ISA) Meeting, Stockholm, June 25-29th 2000
Citation:Expert Opin. Investig. Drugs 2002; 11(1); 125-141
Background: How does rousvastatin compare on key pharmacological parameters to existing statins ?
Study Design:
Aim:This is adapted from a review article by Dr. Michael Davidson
Conclusions:
Rosuvastatin is a potent inhibitor of HMG-CoA Reductase.
Rousvastatin is highly selective for liver.
Rosuvastatin has limited metabolism which does not involve Cyt. P450 3A4 (the major isoenzyme involved in drug metabolism) to any clinically relevant extent and therefore the potential for drug interactions is lowered, since this isoenzyme is involved in the oxidation of a large number of drugs, including the highlighted statins, verapamil, erythromycin and midazolam. (This is shown in more depth in the section dealing with “The clinical pharmacology of rosuvastatin”).
Information from the European Mutual Recognition Summary of Product Characteristics (SmPC):
Cytochrome P450 enzymes: Results from in vitro and in vivo studies show that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a poor substrate for these isoenzymes. No clinically relevant interactions have been observed between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4). Concomitant administration of itraconazole (an inhibitor of CYP3A4) and rosuvastatin resulted in a 28% increase in AUC of rosuvastatin. This small increase is not considered clinically significant. Therefore, drug interactions resulting from cytochrome P450-mediated metabolism are not expected.
Rosuvastatin has a plasma elimination half-life of approximately 19 hours. The elimination half-life does not increase at higher doses.
Presented: Sponsored Symposium at the International Symposium on Atherosclerosis (ISA) Meeting, Stockholm, June 25-29th 2000
Citation:Expert Opin. Investig. Drugs 2002; 11(1); 125-141
Background: How does rousvastatin compare on key pharmacological parameters to existing statins ?
Study Design:
Aim:This is adapted from a review article by Dr. Michael Davidson
Conclusions:
Rosuvastatin is a potent inhibitor of HMG-CoA Reductase.
Rousvastatin is highly selective for liver.
Rosuvastatin has limited metabolism which does not involve Cyt. P450 3A4 (the major isoenzyme involved in drug metabolism) to any clinically relevant extent and therefore the potential for drug interactions is lowered, since this isoenzyme is involved in the oxidation of a large number of drugs, including the highlighted statins, verapamil, erythromycin and midazolam. (This is shown in more depth in the section dealing with “The clinical pharmacology of rosuvastatin”).
Information from the European Mutual Recognition Summary of Product Characteristics (SmPC):
Cytochrome P450 enzymes: Results from in vitro and in vivo studies show that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a poor substrate for these isoenzymes. No clinically relevant interactions have been observed between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4). Concomitant administration of itraconazole (an inhibitor of CYP3A4) and rosuvastatin resulted in a 28% increase in AUC of rosuvastatin. This small increase is not considered clinically significant. Therefore, drug interactions resulting from cytochrome P450-mediated metabolism are not expected.
Rosuvastatin has a plasma elimination half-life of approximately 19 hours. The elimination half-life does not increase at higher doses.
Presented: Sponsored Symposium at the International Symposium on Atherosclerosis (ISA) Meeting, Stockholm, June 25-29th 2000
Citation:Expert Opin. Investig. Drugs 2002; 11(1); 125-141
Background: How does rousvastatin compare on key pharmacological parameters to existing statins ?
Study Design:
Aim:This is adapted from a review article by Dr. Michael Davidson
Conclusions:
Rosuvastatin is a potent inhibitor of HMG-CoA Reductase.
Rousvastatin is highly selective for liver.
Rosuvastatin has limited metabolism which does not involve Cyt. P450 3A4 (the major isoenzyme involved in drug metabolism) to any clinically relevant extent and therefore the potential for drug interactions is lowered, since this isoenzyme is involved in the oxidation of a large number of drugs, including the highlighted statins, verapamil, erythromycin and midazolam. (This is shown in more depth in the section dealing with “The clinical pharmacology of rosuvastatin”).
Information from the European Mutual Recognition Summary of Product Characteristics (SmPC):
Cytochrome P450 enzymes: Results from in vitro and in vivo studies show that rosuvastatin is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a poor substrate for these isoenzymes. No clinically relevant interactions have been observed between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4). Concomitant administration of itraconazole (an inhibitor of CYP3A4) and rosuvastatin resulted in a 28% increase in AUC of rosuvastatin. This small increase is not considered clinically significant. Therefore, drug interactions resulting from cytochrome P450-mediated metabolism are not expected.
Rosuvastatin has a plasma elimination half-life of approximately 19 hours. The elimination half-life does not increase at higher doses.
The studies in the GALAXY Programme are designed to confirm each step in the hypothesis. These are currently:
Studies designed to investigate the effect of CRESTOR on the ‘atherogenic lipid profile’ are STELLAR, MERCURY I, MERCURY II, ORBITAL, DISCOVERY, COMETS, LUNAR, PLUTO, POLARIS and PULSAR. Two of these studies, COMETS and LUNAR also assess the effects of CRESTOR on inflammatory markers.
Studies designed to investigate the effect of CRESTOR on ‘atherosclerosis’ are METEOR, ASTEROID, ORION.
Studies designed to investigate the effect of CRESTOR on ‘cardiovascular morbidity and mortality’ are AURORA, CORONA, JUPITER.
As the GALAXY Programme is constantly evolving new studies will be included as the statin environment changes, research needs dictate and the clinical development of CRESTOR continues.
This slide shows the effect of CRESTOR 10-40 mg, atorvastatin 10-80 mg, simvastatin 10-80mg and pravastatin 10-40mg on LDL-C.
CRESTOR achieved impressive LDL-C reductions at every dose.
CRESTOR 10-40 mg reduced LDL-C by 45.8 – 55.0% compared to 36.8 - 51.1% with atorvastatin 10-80 mg, 28.3- 45.8% with simvastatin 10-80 mg and 20.1 - 29.7% with pravastatin 10-40 mg.
These are LOCF data.
Rosuvastatin 10 mg reduced LDL-C to a significantly greater extent than atorvastatin 10 mg; simvastatin 10, 20 or 40 mg; and pravastatin 10, 20 or 40 mg (p&lt;0.002).
Reference
1. Jones PH et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial) Am J Cardiol 2003;92:152–160
This is a graphical representation of the percentage of patients achieving NCEP ATP-III LDL-C goals in all categories of risk at Week 8.
The NCEP ATP-III LDL-C goals for each patient category are as follows:-
low risk (less than 2 risk factors) - Target LDL-C: &lt;160mg/dL (4.14mmol/L)
medium risk (greater than or equal to 2 risk factors) - Target LDL-C:&lt;130mg/dL (3.36mmol/L)
high risk (patients with CHD or CHD risk equivalent) - Target LDL-C: &lt;100mg/dL (2.59mmol/L)
Baseline mean LDL-C values were similar for all treatment groups, and were as follows (mg/dL):
CRESTOR 10 mg: 165.1
atorvastatin 10 mg: 162.6
atorvastatin 20 mg: 167.1
A statistically significantly greater percentage of patients who received CRESTOR 10 mg reached NCEP ATP-III LDL-C target goal at Week 8 compared with patients who received atorvastatin 10 mg (80% vs 63%, p&lt;0.0001), atorvastatin 20 mg (80% vs 74%, p&lt;0.01).
These are LOCF data.
Presented:Poster at the 73rd European Atherosclerosis Society (EAS) Congress, Salzburg, July 7-10th 2002.
Citation:Am J Cardiol 2003;91(suppl):11C–19C
Background: Although statins have been available for a number of years, there is plenty of evidence from studies such as L-TAP and EUROASPIRE I & II that patients do not reach their cholesterol guideline goals, due to inadequate use of effective doses of statins, particularly because patients may be initiated on the starting doses of statins and not have their dose titrated upwards until the cholesterol goal is reached.
Study Design:
Aim:To compare the effects of rosuvastatin 5mg & 10mg and atorvastatin 10mg on the lipid profile across 3 phase III studies, after 12 weeks.
Population:Patients with type IIa / IIb hypercholesterolaemia
Numbers:See slide
Methodology:Prospectively planned, pooled analysis across 3 phase III studies of similar design. All studies were randomised, double-blind, parallel group, multi-centre trials.
Patients were analysed to Joint European Societies LDL-C goals.
Key Results: (Rosuvastatin 5mg data not shown, as dose is unlicensed in EU)
Rosuvastatin 10mg had significantly greater benefits in reducing LDL-C, non-HDL-C and TC and raising HDL-C than atorvastatin 10mg. Effects on TG were similar between groups. (Not shown here – See Section “Rosuvastatin effects on the atherogenic lipid profile”)
More patients reached Joint European Societies LDL-C goals with rosuvastatin 10mg, compared to atorvastatin 10mg.
Conclusions:
Rosuvastatin 10mg gets more patients to achieve their Joint European Societies LDL-C goal than atorvastatin 10mg. Rosuvastatin 10mg gets more patients to reach their cholesterol goal irrespective of risk category, compared to atorvastatin 10mg.
Core slide
After 8 weeks of treatment, a greater proportion of patients receiving rosuvastatin 10 mg achieved LDL-C levels recommended by the European guidelines compared with those patients receiving atorvastatin 10 mg, simvastatin 20 mg or pravastatin 40 mg (all p&lt;0.0001 versus rosuvastatin 10 mg). A similar pattern was observed for NCEP ATP III goal achievement.
Reference
Schuster H et al. Effects of switching statins on achievement of lipid goals: Measuring effective reductions in cholesterol using rosuvastatin therapy (MERCURY I) study. Am Heart J 2004; 147: 705−712.
Reproduced from Am Heart J 2004; 147: 705–712, with permission from Elsevier.
Core slide
When patients were switched to rosuvastatin 10 mg after 8 weeks, a greater proportion achieved LDL-C levels recommended by the European guidelines than those who maintained treatment with atorvastatin 10 mg, simvastatin 20 mg or pravastatin 40 mg. Furthermore, a greater percentage of patients achieved this goal after switching from atorvastatin 20 mg to rosuvastatin 20 mg compared with those who maintained their original treatment. There were similar improvements in NCEP ATP III goal achievement.
The following number of patients were included in each arm:
R10/R10: 521
A10/R10: 276
A10/A10: 240
A20/R10: 293
A20/R20: 305
A20/A20: 299
S20/R10: 277
S20/S20: 250
P40/R10: 253
P40/P40: 253
References
Schuster H et al. Effects of switching statins on achievement of lipid goals: Measuring effective reductions in cholesterol using rosuvastatin therapy (MERCURY I) study. Am Heart J 2004; 147: 705−712.
Reproduced from Am Heart J 2004; 147: 705–712, with permission from Elsevier.
This slide shows the effect of CRESTOR 10-40 mg, atorvastatin 10-80 mg, simvastatin 10-80mg and pravastatin 10-40mg on HDL-C.
The CRESTOR HDL-C raising effect is maintained across the 10-40 mg dose range unlike the effect seen across the atorvastatin 10-80 mg dose range and the simvastatin 10-80 mg dose range.
CRESTOR 10-40 mg increased HDL-C by 7.6 – 9.6% compared to 2.0 – 5.7% with atorvastatin 10-80 mg, 5.2 – 6.8% with simvastatin 10-80 mg and 3.2 – 5.5% with pravastatin 10-40 mg.
These are LOCF data.
Dose for dose, there were no significant differences in reductions in TG levels from baseline between rosuvastatin and atorvastatin; however, rosuvastatin resulted in a statistically significant greater reduction in TG compared with simvastatin or pravastatin (p&lt;0.002).
Rosuvastatin 10 mg decreased triglycerides statistically significantly more than pravastatin 10 and 20 mg (p&lt;0.002).
Rosuvastatin 20 mg decreased triglycerides statistically significantly more than simvastatin 40 mg, pravastatin 20 and 40 mg (p&lt;0.002).
Rosuvastatin 40 mg decreased triglycerides statistically significantly more than simvastatin 40 mg and pravastatin 40 mg (p&lt;0.002).
Mean baseline TG for rosuvastatin group: 179 mg/dl.
Reference
1. Jones PH, et al. Comparison of the Efficacy and Safety of Rosuvastatin Versus Atorvastatin, Simvastatin, and Pravastatin Across Doses (STELLAR Trial) Am J Cardiol 2003;93:155–160.
Insulin resistance is an impaired metabolic response to our body&apos;s own insulin so that active muscle cells cannot take up glucose as easily as they should. In that situation, the blood insulin levels are chronically higher which inhibits our fat cells from giving up their energy stores to let us lose weight. This disorder is associated with obesity, hypertension, abnormal triglycerides, glucose intolerance (syndrome &apos;X&quot;) and Type 2 diabetes mellitus. Many women with polycystic ovaries have this as well as women who have gestational diabetes in pregnancy. Up to 50% of patients with hypertension are estimated to have insulin resistance. The main problem is that this condition can exist unrecognized and metabolic damage can occur before a full blown Type 2 diabetes is finally diagnosed. Insulin resistant diabetics are 2-5 times more likely to die from heart attack or stroke than are non diabetics.
The tolerability profile of rosuvastatin compares favorably with that of other currently marketed statins. Withdrawals due adverse events is one of the most objective measures of tolerability as it only includes adverse events which were sufficiently severe for medication to be withdrawn. Further more, withdrawals due to adverse events is the more common way of reporting overall tolerability within Prescribing Information (both US and European).
Rosuvastatin had a similar number of adverse events leading to withdrawal as other statins in fixed-dose controlled trials.
Reference
1. Brewer HB. Benefit-Risk Assessment of rosuvastatin 10 to 40 milligrams. Am J Cardiol 2003;92(Suppl):23K-29K.
Effects on muscle are rare but recognised complications of statin therapy. As with other statins, effects on skeletal muscle, e.g. uncomplicated myalgia, myopathy and, rarely, rhabdomyolysis (occasionally associated with impairment of renal function), have been reported in patients treated with rosuvastatin. The incidence of myopathy was low in patients treated with rosuvastatin up to 40 mg (&lt;0.1%) which compares well with that reported within the labels of other currently marketed statins. As with other statins, the risk of myopathy during treatment with rosuvastatin may be increased with concurrent administration of other lipid-lowering therapies, or cyclosporin, or in circumstances which increase rosuvastatin blood levels.In post-marketing experience, the frequency of rhabdomyolysis with rosuvastatin is very rare (&lt;0.01%), which is in line with that reported for the other marketed statins2.Patients should be advised to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by fever or malaise.
References
Brewer HB. Benefit-risk assessment of rosuvastatin 10 to 40 milligrams. Am J Cardiol 2003;92(Suppl):23K–29K
Data on File
The relationship between benefit and risk is a key consideration when assessing any drug. This slide shows available doses for the available statins, expressing percent LDL-C reduction vs percent of patients with CK elevations more than 10 x ULN.
This data taken from a publication by Brewer show that the effect of rosuvastatin on CK elevations is certainly no worse than other statins up to 40 mg, and is combined with better effects on LDL-C reduction. (Rosuvastatin data are from the rosuvastatin clinical developmentl programme, that for the other statins is from independent sources).
Importantly this data highlights the difference between rosuvastatin and cerivastatin in benefit:risk profile. The latter had to push to high doses to achieve only modest LDL-C reductions (the maximum 0.8mg dose of cerivastatin only produced a 42% reduction in LDL-C).
Reference
Brewer HB. Benefit-Risk Assessment of rosuvastatin 10 to 40 milligrams Am J Cardiol 2003;92(Suppl):23K-29K.
Reported Cases of Fatal Rhabdomyolysis and Numbers for All Statins Dispensed in the US Since These Products Were Launched
This slide shows a summary of the clinical experience, through May 2001, of statins in terms of incidence of fatal rhabdomyolysis in the US.
The rate of fatal rhabdomyolysis per 1 million prescriptions ranges from a low of 0 (fluvastatin) to a high of 3.16 for cerivastatin, the latter of which was of course withdrawn from the market in August 2001. Atorvastatin and pravastatin have rates of 0.04 per 1 million prescriptions, simvastatin 0.12 per million, and lovastatin 0.19 per million.
The authors’ results show that fatal rhabdomyolysis is rare among statin users, with reporting rates lower than one death per million perscriptions for most statins. However, the rate of fatal rhabdomyolysis associated with cerivastatin was 16–80 times as high as for any other statin. On the basis of markedly increased reporting rates of fatal rhabdomyolysis associated with cerivastatin, the drug was withdrawn from the US market.
Steffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis [letter to the editor].
N Engl J Med. 2002;346:539-540.
Elevations in liver transaminase levels are an infrequent but recognised complication of treatment with statins.
Incidence of clinically significant increases in serum transaminases* with rosuvastatin 10–40 mg in clinical trials was low (&lt;0.3%) which is similar to that seen with other currently marketed statins.1,2
As with other statins:
it is recommended that liver function tests be carried out prior to initiation and periodically thereafter
rosuvastatin should be used with caution in patients who consume excessive quantities of alcohol and/or have a history of liver disease
rosuvastatin is contraindicated in patients with active liver disease or unexplained persistent transaminase elevations.
*ALT &gt;3 x ULN on 2 successive occasions
Reference
Brewer HB. Benefit-risk assessment of rosuvastatin 10 to 40 milligrams. Am J Cardiol 2003;92(Suppl):23K–29K
Shepherd J et al. Safety of rosuvastatin. Am J Cardiol 2004;94:882-888
The relationship between benefit and risk is a key consideration when assessing any drug. This slide shows available doses for the available statins, expressing percent LDL-C reduction vs percent of patients showing persistent ALT elevation.
This data taken from a publication by Brewer show that the effect of rosuvastatin on the liver (as assessed by ALT elevations) is certainly no worse than other statins up to 40 mg, and is combined with better effects on LDL-C reduction. (Rosuvastatin data are from the rosuvastatin clinical developmentl programme, that for the other statins is from independent sources).
References
1. Brewer HB. Benefit-Risk Assessment of rosuvastatin 10 to 40 milligrams Am J Cardiol 2003;92(Suppl):23K-29K.
Presented: Poster at the 5th Congress of the European Association for Clinical Pharmacology and Therapeutics (EACPT) Meeting, Odense, Denmark, September 12-15th 2001.Poster at the American College of Clinical Pharmacology (ACCP) Meeting, Tampa, Florida, October 21-24th 2001Poster at the 30th Annual Meeting of the American College of Clinical Pharmacology, Vienna, Virginia, September 23r-25th 2001
Citations:Pharmacol Toxicol 2001; 89(Suppl 1):77-78 abs 297Pharmacol Toxicol 2001; 89(Suppl 1):78 abs 298
Pharmacol Toxicol 2001; 89(Suppl 1):75 abs 286
Pharmacol Toxicol 2001; 89(Suppl 1):75 abs 287
Pharmacol Toxicol 2001; 89(Suppl 1):75 abs 288Pharmacotherapy 2001; 21(10): 1255 abs 6
Information from the European Mutual Recognition Summary of Product Characteristics (SmPC):
Vitamin K antagonists: As with other statins, the initiation of treatment or dosage up-titration of rosuvastatin in patients treated concomitantly with vitamin K antagonists (e.g. warfarin) may result in an in INR. Discontinuation or down-titration rosuvastatin may result in a in INR. In such situations, appropriate monitoring of INR is desirable.
Gemfibrozil: As with other statins, resulted in a 2-fold in rosuvastatin Cmax and AUC. (For comparison, lovastatin1 & simvastatin2 have similar increases in exposure, but cerivastatin3 has a 5-fold increase in combination)
Cyclosporin: Rosuvastatin plasma levels were on average 7 times than those observed in healthy volunteers. Concomitant administration did not affect plasma concentrations of cyclosporin.
Antacid: An antacid suspension containing aluminium and magnesium hydroxide resulted in a in rosuvastatin plasma concentration of approximately 50%. This effect was mitigated when antacid was dosed 2 hours after rosuvastatin. Clinical relevance of this interaction has not been studied.
Cytochrome P450 enzymes: In vitro and in vivo studies show that rosuvastatin is neither an inhibitor / inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a poor substrate for these isoenzymes. No interactions have been observed between rosuvastatin and either fluconazole (an inhibitor of CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of CYP2A6 and CYP3A4). Itraconazole resulted ina 28% in AUC, but this small is not considered clinically significant. Therefore, drug interactions resulting from Cytochrome P450-mediated metabolism are not expected.
Erythromycin: Resulted in a 20% in AUC (0-t) and a 30% in Cmax of rosuvastatin. This interaction may be caused by increase in gut motility caused by erythromycin.
Oral Contraceptive / HRT: Resulted in an in ethinyl oestradiol and norgestrel AUC of 26% and 34%, respectively. These plasma levels should be considered when selecting oral contraceptive doses. No pharmacokinetic data exists for HRT, although the combination has been used extensively in clinical trials and was well tolerated
Other medications: There were no clinically relevant interactions with digoxin, fenofibrate
References
Backman JT et al. Clin Pharmacol Ther 2001; 69:340-345
Backman JT et al. Clin Pharmacol Ther 2000; 68:122-129
Backman JT et al. Clin Pharmacol Ther 2002; 72:685-691
