ISoP Training Course- Zagreb, 3-4 April 2014 Medical assessment of drug induced rhabdomyolysis and metabolic disorders Marco Tuccori, ISoP EC member Unit of Adverse Drug Reacon Monitoring University Hospital of Pisa, Pisa, Italy At the forefront of pharmacovigilance around the world 1 ISoP training course Zagreb 3-4 April 2014 Proacve Pharmacovigilance, Risk Management and Pharmacovigilance in the Era of Personalised Medicine All presentaons provided as PDF files are protected by copyright. Prinng and storage is for scholarly research, educaonal and personal use only. Any copyright or other noces or disclaimers must not be removed, obscured or modified. If used for training the original source must be properly credited. Copying and make copies of the PDF presentaons (including through e-mail) are not permied. The PDF files must not be posted on an open- access website. At the forefront of pharmacovigilance around the world 2 Summary • Metabolic adverse reactions • Muscular adverse reactions • Definitions and classifications • Signs and symptoms • Main (alternative) causes • Drugs most frequently involved • Biological plausibility • Drug-induced lipids metabolism alterations • Drug-induced glucose metabolism alterations At the forefront of pharmacovigilance around the world 3 Metabolic Adverse Reacons Metabolism is the set of life-sustain- ing chemical transformations within the cells of living organisms. These enzyme-catalyzed reactions allow organisms to grow and reproduce, maintain their structures, ? and respond to their environments. DRUGS Lipids Myopathies Carbohydrates At the forefront of pharmacovigilance around the world 4 Muscular adverse events Definions and Classificaons Term ACC/AHA/NHLBI NLA FDA Myopathy Any disease of the Symptoms of myalgia (muscle CK > 10 ULN muscle pain or soreness), weakness. Or cramps, plus CK > 10 ULN Myalgia Muscle aches or NA NA weakness without CK elevaon Myosiss Muscle symptoms with NA NA increased CK Rhabdomyolysis Muscle symptoms CK > 10.000 IU/L or CK > 10 ULN CK > 50 ULN, associated with marked plus elevaon in serum creane evidence of organ CK elevaons, pically > or medical intervenon with iv damage, such as renal 10 ULN hydraon compromise ACC/AHA/NHLBI: American College of cardiology/American Heart Associaon/Naonal Heart, Lung and Blood Instute; NLA: Naonal Lung Associaon; FDA: Food and Drug Administraon; NA: not available, ULN: upper limit of normal; CK: crean kinase Joy TR, Hegele RA. Ann Intern Med 2009; 150:858-868 5 Muscular adverse events Mechanisms Myocytes ++ Ca RYR SR ATP ++ Ca++ Ca++ Ca Na+ Na+ Potassium ATP ATP Aldolase + + K K Phosphate ATP Depleon Myoglobin CK Myocytes LDH AST Proteolytic Cell breaks ++ Ca enzyme down activation KIDNEY IMPAIRMENTS Keltz E et al., Musc Lig Ten J 2013;3:303-312 6 Rhabdomyolysis Signs and symptoms Clinical presentation Classic triad: muscle aches, weakness, tea coloured urine Other symptoms: muscular tenderness, swelling, cramps, stiffness Most common muscle groups involved: lower back, thighs and calves Physical examination: limb induration, skin changes due to ischemic damage (not always present) Definitive diagnosis: CK elevations and urine myoglobin At the forefront of pharmacovigilance around the world 7 Creane kinase Creatine kinase (CK), or creatine phosphokinase (CPK) catalyses the conversion of creatine and consumes ATP to create phospocreatine (PCr) and ADP. In tissues and cells that consume ATP rapidly, especially skeletal muscle, PCr serves as an energy reservoir for the rapid buffering and regeneration of ATP in situ. Thus, CK is much expressed in such tissues. Serum CK is the most sensitive indicator of muscle damage. Serum CK begin to rise approximately 2-12 hours after the onset of muscle injury, peaks within 24-72 hours and declines gradually in 7-10 days. At the forefront of pharmacovigilance around the world 8 Myoglobin Myoglobin Plasma globulins Muscle damage 0-0.003 mg/dL Blood Urine 100g of muscle 0.5-1.5 mg/dL tissue degraded Elevated serum myoglobin and myoglobinuria are reliable indicators for rhabdomyolysis but present some limitations: 1) Serum myoglobin levels rise and drop much faster than CK levels (1-6 hours), thus have a low negative predictive value and may not be used as a ruling out test. 2) Myoglobinuria is not always visible or may resolved early (100 mg/dL to cause dark urine). 3) Urine dipstick test also react with the globin fargment of hemoglobin (non specific test) At the forefront of pharmacovigilance around the world 9 Rhabdomyolysis: main causes 1) Increased energy demand Es. Exercise (extreme), Heat stroke, Seizures 2) Decreased energy production Es. Metabolic enzymes deficit, mitochondrial dyfunctions, hypokalemia 3) Direct muscle injuries Es. Crush injury, compartment syndrome, electrical injury, 3°degree burns, temeprature extreme (hyper or hypothermia) 4) Decreased oxygen delivery ES. Arterial thrombus, surgery, prolonged immobilization, trauma, shock 5)Infections 6)Endocrine abnormalities Es. Diabetic keto-acidosis, Addison’s disease, hypo/hyperthyroidsm 7) Toxins (carbon mono-oxide, venoms of snake; spider; wasp) 8) Drugs Es. Substance abuse, barbiturates, benzodiazepins, anaesthetics, neuroleptics, anabolic/corticosteroids, statin/fibrates At the forefront of pharmacovigilance around the world 10 Stans USA TODAY.COM 08/08/2001 Statins: estimate incidence of fatal Updated 12:41 PM ET rhabdomyolysis per milion FDA statement on Baycol withdrawal prescriptions (FDA data) FDA today announced that Bayer Drug Incidence Pharmaceutical Division is voluntarily Cerivastatin 3.16 withdrawing Baycol (cerivastatin) from the Lovastatin 0.19 U.S. market because of reports of sometimes fatal rhabdomyolysis (52 Simvastatin 0.12 cases), a severe muscle adverse reaction Atorvastatin 0.04 from this cholesterol-lowering (lipid- Pravastatin 0.04 lowering) product. The FDA agrees with Fluvastatin 0.00 and supports this decision. Staffa JA et al. N Engl J Med 346, 539, 2002 Risk factors: gender (female), age, Thompson PD et al. JAMA 289, 1681, 2003 concomitant disease (renal and hepatic failure), interactions At the forefront of pharmacovigilance around the world 11 Stans Mechanisms of myopathy (1) Cholesterol reduction in the sarcolemma Statins Mechanic Stress Cholesterol is Cholesterol reduction Membrane weakening important for the in the sarcolemma and rupture maintenance of the integrity of cell Cholesterol membranes Phospholipids Staffa JA et al. N Engl J Med 346, 539, 2002 Bhardwaj S et al., Clin Interven Aging 2013;8:47-59 At the forefront of pharmacovigilance around the world 12 Stans Mechanisms of myopathy (2) Acetyl-CoA HMG-CoA Mevalonate Mevalonate-phyrophosphate Statins HMG-CoA-reductase (-) Isopentenyl-phyrophosphate Lack of prenylation of RabGTPase is Geranyil-phyrophosphate associated with Reduced prenylation vacuolization of muscular of structural and fibers in rat models functional proteins Farnesyl-phyrophosphate (apoptosis) (Sakamoto, 2007) Inhibition of Coenzime Q10 Squalene Lack of ATP formation syntesis and impairment of (energy deficit) the mithocondrial (Marcoff, 2007) respiratory chain Cholesterol Marcoff L et al. J Am Coll Cardiol 49, 2231, 2007 Sakamoto K et al. FASEB J, 21, 4087, 2007 At the forefront of pharmacovigilance around the world Stans Interacons Drug Metabolism Drugs enhancing the risk of myopathy with statins Lovastatin CYP3A4 CYP3A4* inhibitors Simvastatin CYP3A4 CYP3A4* inhibitors Pravastatin Sulphatation - Fluvastatin CYP2C9 (CYP2C8 e CYP3A4) CYP2C9° inhibitors Atorvastatin CYP3A4 CYP3A4* inhibitors Rosuvastatin Limited involvement (10%) of - CYP2C9 and CYP2C19 *Cyclosporin, gemfibrozil, fibrates, azole antimycotics, macrolides antibiotics, protease inhibitors (anti-HIV), grapefruit juice; °Azole antimycotics, protease inhibitors (ritonavir) Armitage J. Lancet 370, 1781, 2007 At the forefront of pharmacovigilance around the world 14 Other drugs Proton Pump Inhibitors Ann Pharmacotherapy 2006;40(2): 352-353 Acute severe myopathy following a single infusion of omeprazole. Tuccori M, Giovannoni S, Giustini SE, Blandizzi C, Del Tacca M. Trazodone Omeprazole Ramipril HCZ Aspirin At the forefront of pharmacovigilance around the world 15 Other drugs Proton Pump Inhibitors Eur J Clin Pharmacol. 2006 Jun;62(6):473-9. Myopathy including polymyositis: a likely class adverse effect of proton pump inhibitors? Clark DW1, Strandell J. 292 reports of various myopathies with PPIs (868 cases of 'myalgia‘ were excluded) Positive dechallenge: 69 patients Positive rechallenge: 5 patients (1 case of a cross reaction with 3 different PPIs) 33% of reports a PPI was the only administered drug Myositis or polymiositis: 27 patients Rhabdomyolisis: 35 patients (9 positive dechallenge) Time to onset of rhabdomyolisis (n = 17): within 1 week (n = 9); 2-12 weeks (n = 3) Cross-sectional slice of human skeletal muscle showing acute muscle fiber In 12 cases of rhabdomyolisis, a statin was taken necrosis (hematoxylin and eosin stain; concomitantly × 400 original magnification). At the forefront of pharmacovigilance around the world 16 Rhabdomyolysis Syndromes Malignant hyperthermia Ryanodine Receptor ALOTANE Exon 44 Massive (anesthetic gases) Gene RyR1 intracellular ++ Rhabdomyolysis Mutation Mutation Ca Ala2350Thr Arg2355Trp HALOPERIDOL release Mutation (Neuroleptic drugs) Gly2355Ala Neuroleptic malignant syndrome At the forefront of pharmacovigilance around the world 17 Other drugs Gabapenn Ann Pharmacotherapy 2007;41(7):1301-5. Gabapentin-induced severe myopathy Tuccori M, Lombardo G, Lapi F, Vannacci