Chemical Structure of Rosuvastatin

1
Chemical Structure of Rosuvastatin
Statin Pharmacophore
Relative lipophilicity
O
Ca
(3R, 5S)
O
H
Cerivastatin
O
Simvastatin
O
H
Fluvastatin
Atorvastatin
F
C
H
3
C
H
3
N
N
Rosuvastatin
C
H
3
N
Pravastatin
S
C
H
3
O
O
log D at pH 7.4
Presented at XXII Congress of European Society of
Cardiology, August 26-30, 2000, Amsterdam, The
Netherlands
2
Inhibition of HMG-CoA Reductase in Human
Catalytic Domain
Rosuvastatin and HMG-CoA reductase activity
50
Significance of difference from rosuva, plt0.05,
plt0.001
Presented at XXII Congress of European Society of
Cardiology, August 26-30, 2000, Amsterdam, The
Netherlands
3
Rosuvastatin Single Dose Pharmacokinetics
100
10
Rosuvastatin plasma concentration (ng/ml)
1
0
10
20
30
40
50
60
70
80
0.1
Time post dose (hours)
Presented at the ISA Meeting, Stockholm, June 2000
4
Systemic Availability
Dose
Tissues
Biliary transport
Systemic Availability () Cmax(ng/ml) Free drug(nM)
Ceriva 60 10 0.2
Simva 5 44 5
Rosuva 20 53 12
Prava Atorva 18 12 50 .. 56 .
Circulation
Absorption
Hepatic Extraction
Renal Clearance
Faecal Elimination
Urinary Excretion
5
Dose-related reductions of LDL-C with
Rosuvastatin
Dose (mg)
P
1
2.5
5
10
20
40
80
10
80
0
-10
-20

-30
Percentage change (SE) from baseline in LDL-C


-40

-50


placebo (P)

-60
rosuvastatin
atorvastatin
-70
Baseline means across study 4.7 5.1mmol/l
(180197mg/dl)
plt0.001 (rosuvastatin vs. placebo)
NB No statistical comparisons were made with
open-label atorvastatin
Olsson AG, Am J Cardiol, 2001 88504-508
6
Rosuvastatin time dependancy of LDL-C Reduction
0
placebo
-10
placebo
-20
Mean percentage change in LDL-C
-30
-40
rosuvastatin 10mg
-50
rosuvastatin 80mg
-60
-70
0
1
2
3
4
5
6
Week
Presented at XXII Congress of European Society of
Cardiology, August 26-30, 2000, Amsterdam, The
Netherlands
7
Rosuvastatin and HDL-C
Dose (mg)
P
1
2.5
5
10
20
40
80
10
80
20
15


10
Percentage change (SE) from baseline in HDL-C
5
0
placebo
-5
rosuvastatin
atorvastatin
-10
Baseline means across study 1.21.5mmol/l
(4558mg/dl)
plt0.05 (rosuvastatin vs. placebo)
NB No statistical comparisons were made with
open-label atorvastatin
Olsson AG, Am J Cardiol, 2001 88504-508
8
Rosuvastatin and plasma TG at 6 weeks in
hypertriglyceridemic patients
Presented at XIV International Symposium on Drugs
Affecting Lipid Metabolism, September 9-12, 2001,
New York, NY, USA