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Rosuvastatin

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Rosuvastatin

  1. 1. New era ofNew era of Dyslipidaemia treatmentDyslipidaemia treatment RovirosRoviros (Rosuvastatin)(Rosuvastatin) Dr Jahanzaib Sheikh Nabi Qasim Pharma
  2. 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. 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. 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. 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. 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. 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. 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. 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. 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. 11. Adult Treatment Panel IIIAdult Treatment Panel III (ATP III) Guidelines(ATP III) Guidelines National Cholesterol Education Program
  12. 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
  13. 13. Relationship betweenRelationship between LDL-CLDL-C andand CV EventCV Event RateRate Adapted from Ballantyne CM et al. Am J Cardiol 1998;82:3Q–12Q. LDL-C achieved mg/dL (mmol/L)LDL-C achieved mg/dL (mmol/L) WOSCOPS - PlWOSCOPS - Pl AFCAPS/TexCAPS - PlAFCAPS/TexCAPS - Pl ASCOT - PlASCOT - PlAFCAPS/TexCAPSAFCAPS/TexCAPS - Rx- Rx WOSCOPS - RxWOSCOPS - Rx ASCOT - RxASCOT - Rx ALLHAT - RxALLHAT - Rx ALLHAT - PlALLHAT - Pl 4S - Rx4S - Rx HPS - PlHPS - Pl LIPID - RxLIPID - Rx 4S - Pl4S - Pl CARE - RxCARE - Rx LIPID - PlLIPID - Pl PROSPER - PlPROSPER - Pl CARE - PlCARE - Pl HPS - RxHPS - Rx PROSPER - RxPROSPER - Rx 00 55 1010 1515 2020 2525 3030 70 (1.8)70 (1.8) 90 (2.3)90 (2.3) 110 (2.8)110 (2.8) 130 (3.4)130 (3.4) 150 (3.9)150 (3.9) 170 (4.4)170 (4.4) 190 (5.0)190 (5.0) 210 (5.4)210 (5.4) Eventrate(%)Eventrate(%) - Secondary prevention- Secondary prevention - Primary prevention- Primary prevention Rx - Statin therapyRx - Statin therapy Pl - PlaceboPl - Placebo
  14. 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. 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. 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) ×
  17. 17. Cholesterol-Lowering Drug TherapyCholesterol-Lowering Drug Therapy HMG CoA Reductase Inhibitors  Lovastatin  Simvastatin  Pravastatin  Atorvastatin  Cerivastatin (2001/8 withdrawal from market)  Rosuvastatin  Pitavastatin  Niacin/Lovastatin  Amlodipine/Atorvastatin  Aspirin/Pravastatin Cholestyramine  Colestipol  Colesevelam Fibrates  Gemfibrozil  Fenofibrate  Clofibrate Nicotinic Acid Ezetimibe
  18. 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. 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. 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. 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. 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. 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
  24. 24. Atorvastatin Simvastatin Pravastatin B M YB M Y Fluvastatin Lovastatin Cerivastatin Rosuvastatin 1991 1987 1993 20001996 1997 2003
  25. 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. 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. 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. 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. 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. 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. 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. 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. 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)
  34. 34. Pharmacokinetic properties of Statins Parameter Rosuva Atorva Fluva Lova Prava Simva Absolute bioavailability,% 20 12 10-35 <5 18 >5 Food effect on bioavailability None ↓13% ↓15-25% ↑50% ↓ 30% None Protein binding, % 90 >98 >99 95 48 95 Hepatic extraction, % dose 90 >70 68 >70 50 78-87 Metabolic enzyme (S, substrate; I, inhibitor) (none) 2C9,2C19 3A4(S) 2C9(I) 3A4(S) Sulfation (none) 3A4(S) Half-life, h 20 14 <1 3-4 1.8 3 Elimination, % Urine Feces 10 90 2 96 5 95 10 70 20 70 13 80 Thomas N. Riley, PhD & Jack DeRuiter, PhD (2004)
  35. 35. ROVIROS® Rosuvastatin is the most effective statin at lowering LDL-C and produces a significant increase in HDL-C
  36. 36. 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
  37. 37. 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.
  38. 38. 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
  39. 39. 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
  40. 40. 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
  41. 41. 0 10 20 30 40 50 60 70 80 90 100 PatientsachievingLDL-Cgoal(%) P<0.01 p<0.0001 Dose (mg/day) 74 63 80 10 10 20 n=535 n=528 n=923 OMNITOR atorvastatin •high risk (with CHD or CHD risk equivalent) - Target LDL-C: <100mg/dL (2.59mmol/L) Baseline mean LDL-C values (mg/dL) OMNITOR 10 mg: 165.1 (4.28 mmol/L) atorvastatin 10 mg: 162.6 (4.21) atorvastatin 20 mg: 167.1 (4.33) RosuvastatinRosuvastatin 10 mg10 mg gets more patients to NCEP ATP- III LDL-C GoalsNCEP ATP- III LDL-C Goals MERCURY I study; Am Heart J 2004; 147: 705-12
  42. 42. **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)
  43. 43. 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
  44. 44. 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)
  45. 45. RosuvastatinRosuvastatin effectively raiseseffectively raises HDL-CHDL-C 11 0 2 4 6 8 10 12 10 20 40 80 Dose (mg) LSmean%changefrombaseline CRESTOR atorvastatin simvastatin pravastatin Log scale STELLAR Study. Am J Cardiol 2003; 92: 152–60.
  46. 46. *p<0.002 vs pravastatin 10, 20 mg **p<0.002 vs simvastatin 40 mg; pravastatin 20, 40 mg †p<0.002 vs simvastatin 40 mg; pravastatin 40 mg Jones PH, et al. Am J Cardiol 2003;92:152–160 –20 –22.6 –26.8 –28.2 –11.9 –17.6 –14.8 –18.2 10 20 40 80 –23.7 ** –26.1 † –19.8 * 10 20 40 10 20 40 80 –8.2 –7.7 –13.2 10 20 40 –30 –25 –20 –15 –10 0 –5 Dose (mg) Rosuvastatin Atorvastatin Pravastatin Simvastatin Change in TG from baseline (%) RosuvastatinRosuvastatin effectively reduceseffectively reduces TG
  47. 47. RosuvastatinRosuvastatin reduces in Inflammatory Markerreduces in Inflammatory Marker CC--RReactiveeactive PProteinrotein (ANDROMEDA)(ANDROMEDA) RSV ATV 10 mg 10 mg RSV ATV 20 mg 20 mg 16 weeks8 weeks -45 -40 -35 -30 -25 -20 -15 -10 -5 0 Meanchangefrom baselineinhsCRP(%) Rosuvastatin (RSV) Atorvastatin (ATV) -34.0-34.0 -21.2-21.2 -39.8-39.8 -33.8-33.8 7474thth EASC 17-20 April 2004, Seville, SpainEASC 17-20 April 2004, Seville, Spain
  48. 48. 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
  49. 49. StatinsStatins –– Therapeutic RatioTherapeutic Ratio Therapeutic Effects Adverse Effects Cardiovascular protection Muscle Liver Drug interactions Benefit Risk
  50. 50. 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
  51. 51. 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
  52. 52. 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(%)
  53. 53. 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)
  54. 54. 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
  55. 55. 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)
  56. 56. 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
  57. 57. 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))
  58. 58. 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
  59. 59.  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
  60. 60. 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
  61. 61. Thanks for your attention !

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