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Rosuvastatin
The document discusses dyslipidemia and cardiovascular disease. It notes that cardiovascular disease is a leading cause of death worldwide and that dyslipidemia, specifically elevated LDL cholesterol, is a major modifiable risk factor. Statins are very effective at lowering LDL cholesterol levels and reducing cardiovascular events, with rosuvastatin being one of the statin drugs discussed as a new treatment option for dyslipidemia.
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Rosuvastatin
- 1. New era ofNewera of Dyslipidaemia treatmentDyslipidaemia treatment RovirosRoviros (Rosuvastatin)(Rosuvastatin) Dr Jahanzaib Sheikh Nabi Qasim Pharma
- 2. Global Burden ofCardiovascular 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 forCardiovascular 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 RiskAssociated 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 MajorRisk 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 MajorRisk 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 38primary 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 Changesin 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 inNeed 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 thatare 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 PanelIIIAdult Treatment Panel III (ATP III) Guidelines(ATP III) Guidelines National Cholesterol Education Program
- 12. LDL Cholesterol LevelsandLDL 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. Relationship betweenRelationship between LDL-CLDL-Candand 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. Update to ATPIII 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 IIILDL 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 IIIGuidelines2004 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. Cholesterol-Lowering Drug TherapyCholesterol-LoweringDrug 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. CholestyramineCholestyramine Mechanism of action Bindbile 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 Asligands 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 Alterlipid 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 ofcholesterol 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 CoAreductase 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 Actionof 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. Atorvastatin Simvastatin Pravastatin B M YBM Y Fluvastatin Lovastatin Cerivastatin Rosuvastatin 1991 1987 1993 20001996 1997 2003
- 25. Only about50% 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 ofFeatures 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 CholesterolSynthesis 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 Istvanand 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 pharmacologyWelldefined 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 ofStatins 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. Pharmacokinetic properties ofStatins 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. ROVIROS® Rosuvastatin is the mosteffective statin at lowering LDL-C and produces a significant increase in HDL-C
- 37. GALAXYGALAXY AURORA CORONA JUPITER ORION (MRI) METEOR ASTEROID (IVUS) STELLAR MERCURYI/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 4080 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 4080 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:versusComparators: 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 patientsat 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
- 42. 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 1020 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
- 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 A20S20 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 mg10mg 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)
- 46. RosuvastatinRosuvastatin effectively raiseseffectivelyraises 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.
- 47. *p<0.002 vs pravastatin10, 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
- 48. RosuvastatinRosuvastatin reduces inInflammatory 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
- 49. Pleiotropic EffectsPleiotropic Effectsofof 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 –– TherapeuticRatioTherapeutic Ratio Therapeutic Effects Adverse Effects Cardiovascular protection Muscle Liver Drug interactions Benefit Risk
- 51. RosuvastatinRosuvastatin Tolerability andSafety –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 andSafetyTolerability 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 - MuscleEffects- 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 ofReportedCases 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 andSafetyTolerability 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 – LiverEffects– 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 InteractionsPotentialDrug 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 Safetyprofile 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 Interactionsof 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 clinicallysignificant 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 ExtensiveClinical 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
- 62.
Editor's Notes
- #3 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.
- #4 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.
- #5 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.
- #6 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.
- #7 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.
- #8 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.
- #9 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
- #10 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
- #11 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
- #13 mmol/L LDL /0.0259 = mg/dL LDL
- #14 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.
- #16 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.
- #24 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.
- #28 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.
- #29 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.
- #30 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.
- #31 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.
- #32 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.
- #33 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.
- #34 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.
- #35 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.
- #38 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.
- #39 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.
- #41 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
- #43 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.
- #44 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.
- #45 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.
- #46 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.
- #47 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.
- #48 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.
- #50 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.
- #52 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.
- #53 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
- #54 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.
- #55 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.
- #56 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
- #57 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.
- #61 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