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2. RISE AND FALL OF LIPOBAY SADAF RIAZ; QU ID: 201305364 13AY_PHAR625 2014-01-01 3. CONTENT Introduction Discovery Pre-clinical trials Clinical trials Phase I Phase IIA Phase IIB/III Phase IV (post-marketing) Withdrawal1/3/20143 4. WHAT IS LIPOBAY?Cerivastatin Sodium Manufacturer: Bayer C26H33FNO5Na Molecular weight is481.5 Class: HMG CoA reductase inhibitors 1/3/20144 5. MOA1/3/20145 6. SOME MARKETED HMG COA REDUCTASE INHIBITORS StatinBrand nameDerivationAtorvastatinLipitor, TorvastSyntheticFluvastatinLescol, Lescol XLSyntheticPitavastatinLivalo, PitavaSyntheticRosuvastatinCrestorSyntheticLovastatinMevacor, Altocor, AltoprevFermentation-derived.MevastatinCompactinPravastatinPravachol, Selektine, LipostatSimvastatinZocor, LipexNaturally occurring compound. Fermentation-derived. (Nocardia autotrophica). Fermentation-derived. (Aspergillus terreus) 1/3/20146 7. BIG PICTURE1/3/20147 8. DISCOVER Y 9. SYNTHESISJournal of Medicinal Chemistry. 1990;33(1):52-60.1/3/20149 10. Compounds 2 were obtained through Wittig reaction with the chiral aldehyde 5 and ylides generated from the phosphoium salts 6, followed by cleavage of the lactol ether moiety of &, oxidation of 9 to lactones 11, and desillylation. Z-configured analogues were prepared through the general sequence 8-> 10 -> 12 -> 31/3/201410 11. PRE-CLINICAL STUDIES 12. PRE-CLINICAL STUDIES Primary effects: In-vitro microsomal fraction of ratlivers L, S, Pr, CCerivastatin was most potent IC50 values Cerivastatin 1.1 nM Simvastatin 66 nM Lovastatin 77 nM, and Pravastatin 176 nM1/3/201412 13. IN VIVO MODEL1/3/201413 14. P/K; ADME DATA Absorption: Complete absorption after oraladministration High hepatic selectivity Metabolism: Hepatic Excretion: Hepatic and renal route1/3/201414 15. PHASE I 16. PHASE I: CLINICAL PHARMACOLOGY Healthy volunteers Metabolism: mainly in theliver; 3 active metabolites (active): M1, M23, and M21/3/201416 17. PHASE IIA 18. DOSE-RANGING AND DOSE-SCHEDULING STUDIES 2 pilot US and European dose-ranging studies, and 1 US dose-scheduling study To establish a dosage regimen and effective therapeutic doses ofcerivastatin in the treatment of hypercholesterolemia. CONCLUSION: The results of the Phase IIa studies on cerivastatin show that inthe range of 0.025 0.2 mg/day is well tolerated and produces significant and consistent dose-dependent reductions in LDL cholesterol, total cholesterol, and apo B, together with modest decreases in triglycerides and increases in HDL cholesterol.1/3/201418 19. PHASE IIB/III 20. CLINICAL EFFICACY AND SAFETY OF CERIVASTATIN EUROPEAN STUDY:CERIVASTATIN Vs SIMVASTATIN Doses of up to 0.2 mg/day produces clinically useful reductions inLDL cholesterol in patients with primary hypercholesterolemia. its A/E profile was similar to that of simvastatin. CANADIAN DOSE-TITRATION STUDY: CERIVASTATIN Vs SIMVASTATIN (Long term) EUROPEAN HIGHER-DOSE STUDY Dose of 0.4 mg/day, significantly greater reductions in LDL cholesterolare achieved without any negative impact on safety and tolerance.1/3/201420 21. CLINICAL EFFICACY AND SAFETY OF CERIVASTATIN Compared with placebo and active comparator statins (lovastatin,simvastatin, and pravastatin) after both short- and long-term administration. Overall, the studies showed that at doses of 0.0250.4 mg/day, cerivastatin produced dose-dependent reductions in LDL cholesterol and total cholesterol, which were significantly greater than placebo.These studies indicate that cerivastatin is a safe and effective long-term treatment for patients with primary hypercholesterolemia and also suggest that higher doses should be investigated.1/3/201421 22. PHASE IV: POST MARKETING 23. POST MARKETING DATA Spontaneous ADRs Reports 100Spontaneous reports Up to 8 August 2001 a total of 5,667 reports containing 11,637 suspected ADRs associated with the use of cerivastatin had been received by Bayer global drug safety.806040 29 20161412 8701/3/201423 24. RHABDOMYOLYSIS Higher reporting rates wereseen as the dose of cerivastatin was increased (0.4mg, 0.8 mg) The reporting rates of confirmed and suspected cases of rhabdomyolysis (6489) in association with cerivastatin monotherapy is greater than that seen with any of the other statins. (FDA AERS, 2000)Suspected cases of rhabdomyolysisConfirmedOthers 49% Unconfirmed 28%1/3/201424 25. In 1999, FDA issued a warning against the useof cerivastatin in combination with gemfibrozil due to increase risk of rhabdomyolysis, which resulted in an addition in the contraindications on the drugs label Still, physician continued to prescribecerivastatin in combination therapy1/3/201425 26. COMBINATION THERAPY The WHO database contains 546 reports ofrhabdomyolysis associated with the use of cerivastatin. Cerivastatin + fibrates (primarily gemfibrozil) = higher reporting rate.CG55%! (302)1/3/201426 27. FATAL CASES Marketing till withdrawal: Confirmed rhabdomyolysis cases had a (n=99) 7.6% fatality rate.Death related to rhabdomyolysis0 14.30% Related 52%The majority of reported fatal cases occurred in 2001 (70.51%).33.70%Possibly related Not related1/3/201427 28. SUMMARY 52 deaths were attributed to drug-related rhabdomyolysis that lead to kidney failure. The risk was found to be higher among patients who received the full dose (0.8 mg/day) and those who received gemfibrozil concomitantly. Rhabdomyolysis was 10 times more common with cerivastatin than the other five approved statins.1/3/201428 29. WITHDRAWAL The manufacturer of lipobay, BayerPharmaceuticals, recalled the drug from the U.S. market following the discovery of these potential side effects and the concern that surrounded them. The withdrawal was initiated on August 8, 2001, only four years after the drug was approved and welcomed onto the market.1/3/201429 30. Those that had beenaffected by lipobay, or the family members of those that died from the side effects of the drug were advised to seek legal assistance. The company has so far paid $842 million to settle 2,224 cases but still faces 9,948 more lipobay cases.1/3/201430 31. REFERENCES 1. Beck G, Kesseler K, Baader E, Bartmann W, Bergmann A, Granzer E, et al. Synthesis and biological activity of new HMG-CoA reductase inhibitors. 1. Lactones of pyridine- and pyrimidine-substituted 3,5-dihydroxy6-heptenoic (-heptanoic) acids. Journal of Medicinal Chemistry. 1990;33(1):52-60. 2. Bischoff H, Heller AH. Preclinical and clinical pharmacology of cerivastatin. The American Journal of Cardiology. 1998;82(4, Supplement 2):18J-25J. 3. Hunninghake DB. Clinical efficacy of cerivastatin: phase IIa doseranging and dose-scheduling studies. The American Journal of Cardiology. 1998;82(4, Supplement 2):26J-31J. 4. Davignon J, Hanefeld M, Nakaya N, Hunninghake DB, Insull Jr W, Ose L. Clinical efficacy and safety of cerivastatin: summary of pivotal Phase IIb/III studies. The American Journal of Cardiology. 1998;82(4, Supplement 2):32J-9J. 5.http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_docu ment/Cerivastatin_36/WC500011752.pdf 1/3/201431 32. STRUCTURE ACTIVITY RELATIONSHIP (SAR) The inhibitory potency strongly depends upon the substitution pattern of the heteroaromatic ring Substitution 2, 4, 6 position leads to strong biological activity Biological activity reaches a max if an isopropyl group is introduced in position 2 of the central heteroaromatic ring Polar substitution in position 4 results in higher activity Introduction of bulky alkyl groups or phenyl moieties in position 6 results in marked increase of potency1/3/201432