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mevalonate pyrophosphate
isopentenyl pyrophosphate
geranyl pyrophosphate
cholesterol
Aspergillus terreus The oyster mushroom, naturally contains lovastatin.
Joseph Goldstein, who won the Nobel Prize for related work on cholesterol,
said of Endo: "The millions of people whose lives will be extended through
statin therapy owe it all to Akira Endo.”
High level of evidence was found that statins reduce total mortality in
individuals with a history of prior ASCVD events (e.g., secondary
prevention settings).
NLA 2015
National Lipid Association Recommendations forPatient-Centered
Management of Dyslipidemia Terry A. Jacobson and others published in
Journal of Clinical Lipidology
ADA 2014
American Diabetes Association. Standards of medical care in
diabetes.
KDIGO 2015
Kidney Disease Outcomes Quality Initiative
NCEP NCEP NCEP
ATP I ATPIII ATP IV
1988 2001 2013??
NCEP ACC/AHA
NCEP ATP III 2013
ATP II REVISED
1993 2004
Individuals with
Individuals ≥ 21 years of age
clinical Atherosclerotic
with primary LDL-C ≥ 190 mg/dl
Cardiovascular Disease (ASCVD)
IIa
IB IB
B
LDLcholesterol
Diabetes 70-189 mg/dl
<40 yrs,
Age 40-75 yrs >75yrs
IA IIa B IIa C
Patients without LDLcholesterol
diabetes,primary 70-189 mg/dl
prevention
10 yr ASCVD >7.5
risk estimate % 5-7.5%
geranyl pyrophosphate
cholesterol
Fluvastatin
Atorvastatin Rosuvastatin
Pravastatin
BM Y
Lovastatin
Cerivastatin
Simvastatin
Rosuvastatin:
A new hydrophilic statin – single enantiomer
Statin Pharmacophore
Relative lipophilicity *
O Ca 2.0
(3R, 5S) HO cerivastatin
O simvastatin
1.5
OH fluvastatin
1.0 atorvastatin
F
CH3 0.5
CH3 0.0
N N rosuvastatin
-0.5
H3C N pravastatin
-1.0
S CH3
O O * log D at pH 7.4
140
120
% of Control Fibroblasts IC50= 331 nM
Mean Hepatocytes IC50= 0.2 nM
100
80
60
40
20
0
0 0.1 1 10 100 1000 10000 100000
Concentration (nM)
Buckett et al., (2000)
Cerivastatin: Non hepatoselective
Cholesterol synthesis inhibited in fibroblasts
and hepatocytes at similar concentrations
Inhibition of Cholesterol Synthesis in Rat Hepatocytes and Rat Fibroblasts
140
120
% of Control Fibroblasts IC 50= 1.3 nM
Mean Hepatocytes IC50= 2.4 nM
100
80
60
40
20
0
0 0.01 0.1 1 10 100 1000 10000 100000
Concentration (nM)
Buckett et al., (2000)
Rosuvastatin : X-Ray crystallography provides
molecular rationale for potent enzyme inhibition
The rosuvastatin:
HMG-CoA reductase
complex has more
bonding interactions
than any other statin
binding interaction
Arg568 and sulphone
Prava ***
44.1
100
*P<0.05 vs Rosuvastatin; ***P<0.001 vs Rosuvastatin
McTaggart et al., (2001)
Pharmacologic properties of Statins
Lipophilicity
-0.3 +4.1 +3.2 +4.3 -0.2 +4.7
(log P)
IC50(nm)
5 8 28 NA NA 11
Potency
Elimination, %
10 2 5 10 20 13
Urine 90 96 95 70 70 80
Feces
Rosuvastatin
Atorvastatin
Simvastatin
10 20 40
mg mg mg
* † ‡
10 20 40 80
mg mg mg mg
Rosuvastatin
Atorvastatin
10 20 40 80 Simvastatin
mg mg mg mg Pravastatin
10 20 40
mg mg mg Rosuvastatin 10 mg (–46%)
*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
100%
P-values
***p<0.002
90% CRESTOR 10 mg
vs. atorvastatin
% patients reaching LDL-C goal*
10 mg pravastatin
10, 20 & 49 mg and
80% * simvastatin 10, 20,
80 mg & 40 mg
70%
40 mg
10 mg
80 mg
60% Usual start doses
20 mg
50%
40 mg
10 mg
40%
20 mg
30%
20% 40 mg
10 mg
n=160
10% n= n= n= 20 mg
156 158 158
10 mg
CRESTOR atorvastatin simvastatin pravastatin
80 OMNITOR
80 atorvastatin
70 74
60 63
50
40 Baseline mean LDL-C values (mg/dL)
OMNITOR 10 mg: 165.1 (4.28 mmol/L)
20
10
(%)
*** ***
80 85
81 82
60 64
51
40 49
20
100 *
90 *
88
84 *
80
76
70
69
Patients 62
at goal 60
(%) 50
40
30
20
10
0
R10 A10 A20 S20 P40
*p<0.0001 (R10 vs A10, S20 & P40) 1998 European goal <3.0 mmol/l (116 mg/dl)
Patients 60
at goal
50
(%)
40
30
20
10
0
AD1o0seA(m10g) A20 A20 A20 S20 S20 P40 P40
R10 A10 R10 R20 A20 R10 S20 R10 P40
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
Pleiotropic Effects of Rosuvastatin
in 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
Statins – Therapeutic Ratio
Adverse Effects
Therapeutic
Effects
Muscle
Liver
Cardiovascular
protection Drug interactions
Tolerability and Safety –
Withdrawals due to Adverse Events
10
Percentage of patients with an adverse event
9 leading to withdrawal
8
7
6
Percentage of
5
4
patients
2.9% 3.2%
3 2.5% 2.5%
2
10-80 mg
10-40 mg 10-80 mg 10-40 mg
1
0
rosuvastatin atorvastatin simvastatin pravastatin
(n=3074) (n=2899) (n=1457) (n=1278)
1.5
1.0
0.5
0.0
20 30 40 50 60 70
LDL-C reduction (%)
Fatal cases of 19 3 14 0 6 31 0
rhabdomyolysis
No. of
prescriptions 99,197 81,364 116,145 37,392 140,360 9,815 10,100
dispensed since
marketing began
(in thousands)
*worldwide prescriptions
#Netherlands (MR ref state)
Adapted from: Steffa JA, et al. N Engl J Med. 2002;346:539-540.
Tolerability and Safety
- Liver Effects
2.0
1.5
1.0
0.5
0.0
20 30 40 50 60 70
LDL-C reduction (%)
Persistent elevation is elevation to >3 x ULN on 2 successive occasions
Contraindication:
• Cyclosporin – 7x increase in rosuvastatin AUC
• ANY fibrate with rosuvastatin 40 mg
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)
The GALAXY Program