Rosuvastatin-Internal Medical Training.pptx

Rosuvastatin Induction medical training For internal use only and are not to be shown or disseminated outside of Astrazeneca Lipids Lipids are fat or fat-like substances that are insoluble in water and are important dietary constituents with many funct...

Rosuvastatin Induction medical training For internal use only and are not to be shown or disseminated outside of Astrazeneca Lipids Lipids are fat or fat-like substances that are insoluble in water and are important dietary constituents with many functions. Major source of energy. Include simple lipids (cholesterol, fatty acids) and complex lipids (triglycerides). Cholesterol is a soft waxy lipophilic substance present in all cells of the body. The body synthesises most of the cholesterol it uses in the liver and small intestine. The remaining cholesterol is obtained from dietary animal sources. Cholesterol is important for the repair of cell membranes, the synthesis of steroid hormones, vitamin D and bile acids. Apolipoproteins permit the transport of cholesterol and other water- insoluble lipids within the body. Lipoproteins are macromolecular aggregates of lipids and apolipoproteins and allow lipids to be carried in the blood. Classified according to their density, size and composition: - Chylomicrons and VLDL (triglyceride rich) - LDL Maxfield, and F.R., HDL Tabas, (cholesterol I., 2005. rich) Role of cholesterol and lipid organization in disease. Nature 438, 612–621. Rezen, T., Rozman, D., Pascussi, J.M., Monostory, K., 2011. Interplay between cholesterol and drug metabolism. Biochim. Biophys. Acta 1814, 146– 160. 2  C14607 Cholesterol & Lipoproteins Cholesterol, due to its hydrophobic nature, cannot dissolve in the blood, and is instead transported to and from the liver by carrier proteins called Surface phospholipids lipoproteins. Core triglyceride Free cholesterol & cholesterol ester Apolipoproteins Lipoproteins act as a “fuel delivery” vehicle in order to deliver the “cargo” (the lipids) to the periphery Adapted from Hyperlipidemia. (2005) Third edition; Health Press Ltd: Page 8  C14607 Lipoproteins Differentiation Core Lipid Composition Chylomicron LDLC HDLC LPL HL ApoB48 ApoB100 ApoB100 ApoB100 ApoAI Tg CE CE Tg Tg Tg CE CE CE Tg VLDL IDL LDL Triglyceride rich cholesterol rich Adapted from Hyperlipidemia. (2005) Third edition; Health Press Ltd: Page 10 Lipoproteins VLDL are produced in the liver and are the main carriers of endogenous (non dietary) triglycerides and cholesterol to sites for use or storage. - As the triglycerides are removed, the VLDL remnants continue to circulate as LDL particles. LDL particles are the principal lipoproteins involved in atherosclerosis and are the main carriers of cholesterol. Oxidised LDL is the most atherogenic form of LDL HDL particles are the smallest and most abundant lipoprotein and are protective against atherosclerosis. - Return 20-30% cholesterol in the blood to the liver from the peripheral tissues for excretion - Inhibit the oxidation of LDL - Decrease the attraction of macrophages to the artery wall NCEP.JAMA 2001; 285: 2486-97 De Backer G. Eur Heart J 2003; 24: 1601-10 Austin MA. Am J Cardiol 1998; 81 (4 Suppl.): 7B-12B Sacks FM. Am J Cardiol 2002; 90: 139-43 Salonen JT. Circulation 1991; 84: 129-39 Assmann G. Atherosclerosis. 1996; 124 Suppl.: S11- 20 5  Apolipoproteins Protein content of lipoproteins ApoB levels used to estimate LDL particle number and increased CVD risk ApoA-I – major apolipoprotein in HDL and is linked to reduced CVD risk Functions of apolipoproteins include: – facilitation of lipid transport – activation of three enzymes in lipid metabolism lecithin cholesterol acyltransferase (LCAT) lipoprotein lipase (LPL) hepatic triglyceride lipase (HTGL) References 1. In: Statins - The HMG-CoA Reductase Inhibitors in Perspective. Eds Gaw A, Packard CJ, Shepherd J. Martin Dunitz 2000, 1–19. 2. In: Fast Facts -– binding Hyperlipidaemia. to cell Eds Durrington surface P, Sniderman receptors A. Health Press Ltd, Oxford, Second Edition, 2002. 7–12. Disease area: Atherosclerosis Atherosclerosis is a progressive disease and is a condition in which fat, cholesterol and other substances collect along the walls of medium and large arteries to form hard structures called plaques. The pathogenesis has two main elements: the excessive accumulation of arterial lipids due to abnormal lipoprotein metabolism and smooth muscle cell proliferation in response to endothelial damage. This leads to narrowing of the arteries and reduced blood flow. Plaques can disintegrate and pieces can travel to smaller blood vessels leading to blockage and tissue damage or tissue death or blood clots can form around a tear in a plaque resulting in reduced blood flow: results can be a heart attack or stroke. In some cases the atherosclerotic plaque can weaken the artery wall resulting in an aneurysm. Atherosclerosis eventually leads to cardiovascular disease (CVD). Clinical manifestations of CVD include: - Coronary heart disease (CHD)(angina pectoris, MI, sudden cardiac death), a major cause of death in industrialised countries - Cerebrovascular disease (Transient Ischaemic Attacks (TIAs) and stroke) - Peripheral vascular disease (intermittent claudication and gangrene) Lowering the body’s cholesterol levels therefore reduces the risk of having major cardiovascular events such as heart attacks and strokes. Kannel, W.B et al.1979. Ann. Intern. Med. 90, 85–91. Liu, J et al, 2006. Am. J. Cardiol. 98, 1363–1368. 7 Atherosclerosis: C An Inflammatory Disease III.2 © 2002 PPS®  Macrovascular Complications are Diseases of the Large Blood Vessels Atherosclerosis Peripheral vascular Cerebrovascular disease Cardiovascular disease disease Peripheral arterial Myocardial Stroke disease infarction Fowler M, et al. Clin Diabetes 2008;26:77–82 Risk factors for atherosclerosis Diabetes Hypertension High fat diet Heavy alcohol use Increasing age High blood cholesterol Obesity Personal or family history of heart disease Smoking Ascaso JF. Am J Cardiovasc Drugs 2004; 4 (5): 299-314 10  C14607 Diagnosis of Acute Coronary Syndrome (ACS) Chest pain Entry Working diagnosis Acute coronary syndrome ECG ST elevation No ST elevation Troponin Troponin Troponin Biochemistry positive positive negative Final Diagnosis STEMI NSTEMI Unstable angina Adapted from The Cardiovascular System at a Glance. 2nd Edition. Blackwell Publishing. Page 82 Role of the liver The liver plays an important role in cholesterol homeostasis. The liver facilitates clearance of VLDL particles and cholesterol- containing chylomicron (CM) remnants, synthesizes cholesterol, synthesizes and secretes HDL particles, secretes cholesterol and bile salts to bile and is involved in reverse cholesterol transport (RCT). Mariëtte Y.M. van der Wulp. Molecular and Cellular Endocrinology 368 (2013) 1–16 Glomset, J.A., 1970. Am. J. Clin. Nutr. 23, 1129–1136 13 Lipid transportation Lipids are transported through three different pathways: Exogenous: transport of lipids from food to cells. Endogenous: LDL particles formed from VLDLs are removed via hepatic LDL receptors RCT: cholesterol is removed from body tissues (mediated mainly by HDL) and returned to liver for excretion via bile. Glomset, J.A., 1970. Am. J. Clin. Nutr. 23, 1129–136. M.Y.M. van der Wulp et al. Molecular and Cellular Endocrinology 368 (2013) 1–16 14 Dyslipidaemias Abnormalities in the serum level of lipids including overproduction or deficiency. Classified into primary and secondary. Abnormal serum lipid profile may include high total cholesterol, high triglycerides, low high-density lipoproteins (HDL) cholesterol and elevated low-density high-density (LDL) cholesterol. Historically classified by pattern of elevation in lipids and lipoproteins (Fredrickson phenotypes). Diagnosis by serum lipid profile. Inherited genetic defect in primary dyslipidaemias. High LDL cholesterol, high triglyceride and low HDL cholesterol is associated with a high risk of development of CVD. Ascaso JF. Am J Cardiovasc Drugs 2004; 4 (5): 299-314 Fredrickson RI. NEJM 1967;276 15  Classification of Dyslipidaemias: Fredrickson (WHO) Classification Phenotype Lipoprotein Serum Serum Atherogenicity Prevalence elevated cholesterol TG I Chylomicrons mean to None seen Rare IIa LDL mean +++ Common IIb LDL and VLDL +++ Common III IDL +++ Intermediate IV VLDL mean to + Common V VLDL and mean to + Rare chylomicrons LDL – low-density lipoprotein; IDL – intermediate-density lipoprotein; VLDL – very low-density lipoprotein. (High- density lipoprotein (HDL) cholesterol levels are not considered in the Fredrickson classification.) Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379–391.  Familial Hypercholesterolaemia (FH) Most common genetic disorder in Europe and the US Caused by a mutation of the LDL receptor Increases risk of CVD Two types of FH: – Heterozygous FH one LDL-receptor gene affected affects about 1 in 500 people TC 9.0-14.0 mmol/L (360-560 mg/dL) in adulthood – Homozygous FH both LDL-receptor genes affected rare – affects about 1 in 1,000,000 people Reference TC Eds 1. In: Fast Facts - Hyperlipidaemia. 15.0-30.0 Durrington P, Snidermanmmol/L A. Health Press Ltd, (600-1200 Oxford, Second Edition, 2002. 34–47. Visible Signs of FH A- Xanthelasma B – Corneal arcus (Arcus senilis) C - Achilles tendon xanthomas D - Tendon xanthomas E - Tuberous xanthomas F - Palmar xanthomas  The Metabolic Syndrome and Associated CVD Risk Factors Hypertension Abdominal obesity Atherosclerosis Hyperinsulinaemia Insulin Resistance Diabetes Hypercoagulability Endothelial Dyslipidaemia Dysfunction high TGs small dense LDL low HDL-C Deedwania PC. Am J Med 1998;105(1A);1S-3S.  NCEP ATP III Definition of the Metabolic Syndrome Recommends a diagnosis when  3 of these risk factors are present Risk Factor Defining Level Abdominal obesity (Waist circumference) Men >102 cm (>40 in) Women >88 cm (>35 in) TG  150 mg/dL (1.7 mmol/L) HDL-C Men 160 mg/dL along with a positive family history of premature cardiovascular disease (CVD) or two or more other CVD risk factors. reduce LDL‑C, Total‑C, nonHDL‑C and ApoB in children and  1.3Hypertriglyceridemia CRESTOR is indicated as adjunctive therapy to diet for the treatment of adult patients with hypertriglyceridemia. 1.4Primary Dysbetalipoproteinemia (Type III Hyperlipoproteinemia) CRESTOR is indicated as an adjunct to diet for the treatment of adult patients with primary dysbetalipoproteinemia (Type III Hyperlipoproteinemia). 1.5Adult Patients with Homozygous Familial Hypercholesterolemia CRESTOR is indicated as adjunctive therapy to other lipid-lowering treatments (e.g., LDL apheresis) or alone if such treatments are unavailable to reduce LDL‑C, Total‑C, Crestor PI and ApoB in adult patients with homozygous 1.6 Slowing of the Progression of Atherosclerosis CRESTOR is indicated as adjunctive therapy to diet to slow the progression of atherosclerosis in adult patients as part of a treatment strategy to lower Total‑C and LDL‑C to target levels. 1.7 Primary Prevention of Cardiovascular Disease In individuals without clinically evident coronary heart disease but with an increased risk of cardiovascular disease based on age ≥50 years old in men and ≥60 years old in women, hsCRP ≥2 mg/L, and the presence of at least one additional cardiovascular disease risk factor such as hypertension, low HDL‑C, smoking, or a family history of premature coronary heart disease, CRESTOR is indicated to: -reduce the risk of stroke -reduce the risk of myocardial infarction -reduce the risk of arterial revascularization procedures Severe renal impairment (not on hemodialysis): Starting dose is 5 mg, not to exceed 10 mg Cyclosporine: Combination increases rosuvastatin exposure. Limit CRESTOR Crestor PI dose to 5 mg once daily  General Dosing Information The dose range for CRESTOR in adults is 5 to 40 mg orally once daily. Dosing in Asian Patients In Asian patients, consider initiation of CRESTOR therapy with 5 mg once daily due to increased rosuvastatin plasma concentrations. The increased systemic exposure should be taken into consideration when treating Asian patients not adequately controlled at doses up to 20 mg/day 35 Author | 00 Month Year Set area descriptor | Sub level 1  Use with Concomitant Therapy: Patients taking cyclosporine The dose of CRESTOR should not exceed 5 mg once daily Patients taking gemfibrozil Avoid concomitant use of CRESTOR with gemfibrozil. If concomitant use cannot be avoided, initiate CRESTOR at 5 mg once daily. The dose of CRESTOR should not exceed 10 mg once daily Patients taking atazanavir and ritonavir, lopinavir and ritonavir, or simeprevir Initiate CRESTOR therapy with 5 mg once daily. The dose of CRESTOR should not exceed 10 mg once daily 36 Author | 00 Month Year Set area descriptor | Sub level 1  CONTRAINDICATIONS: CRESTOR is contraindicated in the following conditions:  Patients with a known hypersensitivity to any component of this product. Hypersensitivity reactions including rash, pruritus, urticaria, and angioedema have been reported with CRESTOR  Patients with active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels  Pregnancy  Lactation. Limited data indicate that CRESTOR is present in human milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require CRESTOR treatment should not breastfeed their infants 37 Author | 00 Month Year Set area descriptor | Sub level 1  Skeletal Muscle Effects Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including CRESTOR. Myalgia, myopathy and, rarely, rhabdomyolysis have been reported with all doses and in particular with doses > 20 mg. Very rare cases of rhabdomyolysis have been reported with the use of ezetimibe in combination with HMG-CoA reductase inhibitors. Caution with their combined use. Rhabdomyolysis associated with Crestor 40 mg dose. 38 Author | 00 Month Year Set area descriptor | Sub level 1  Liver Enzyme Abnormalities It is recommended that liver enzyme tests be performed before the initiation of CRESTOR, and if signs or symptoms of liver injury occur. Increases in serum transaminases [AST (SGOT) or ALT (SGPT)] have been reported with HMG‑CoA reductase inhibitors, including CRESTOR. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy In a pooled analysis of placebo-controlled trials, increases in serum transaminases to >3 times the upper limit of normal occurred in 1.1% of patients taking CRESTOR versus 0.5% of patients treated with placebo. 39 Author | 00 Month Year Set area descriptor | Sub level 1  Proteinuria and Hematuria These findings were more frequent in patients taking CRESTOR 40 mg, when compared to lower doses of CRESTOR or comparator HMG‑CoA reductase inhibitors, though it was generally transient and was not associated with worsening renal function. Concomitant Coumarin Anticoagulants Caution should be exercised when anticoagulants are given in conjunction with CRESTOR because of its potentiation of the effect of coumarin-type anticoagulants in prolonging the prothrombin time/INR. In patients taking coumarin anticoagulants and CRESTOR concomitantly, INR should be determined before starting CRESTOR and frequently enough during early therapy to ensure that no significant alteration of INR occurs 40 Author | 00 Month Year Set area descriptor | Sub level 1  Pharmacokinetics in healthy subjects Peak plasma concentration of CRESTOR occurs at 4 to 5 hours (tmax). The terminal half-life is from 19 hours (t1/2). On multiple dosing, steady-state was reached within 5 days. Approximately 90% of CRESTOR is bound to plasma proteins, mainly to albumin. The absolute bioavailability is approximately 20% In vitro studies in human hepatic microsomes showed that the limited metabolism of CRESTOR was very slow and that cytochrome P450 (CYP450) 2C9 was the primary metabolic isoenzyme involved, with contribution from CYP2C19. 41  Drug Interactions Fold increase Simvastat Lovastat Atorvas Fluva Cerivas Prava Rosuvast of statin AUC in in tatin statin tatin statin atin Itraconazole 5-20 5-20 2-4 -