RISK FACTORS AND DRUG TO STATIN-INDUCED MYOPATHY

Transcription

1 RISK FACTORS AND DRUG INTERACTION PREDISPOSING TO STATIN-INDUCED MYOPATHY Assist. Prof. Dr. Verawan Uchaipichat Clinical Pharmacy Department Khon Kaen University Advanced Pharmacotherapy 2012

2 Updated d safety-labeling li changes for simvastatin (6 June 2011) for simvastatin (6 June 2011)

3 Key components of recent safetylabeling changes for simvastatin (NEJM 2011; 365: 285-7) 1. Use of the 80-mg dose of simvastatin should be restricted to patients who have been taking it for a long time (i.e., 12 months or more) without S&S of clinically significant muscle toxicity 2. Pts who are currently taking 80-mg dose of simvastatin without adverse effect but who need to begin taking an interacting drug that is contraindicated should be switched to an alternative statin with less potential for DDI

4 Key components of recent safetylabeling changes for simvastatin (NEJM 2011; 365: 285-7) 3. Pts in whom the LDL-C goal cannot be achieved with a 40-mg dose of simvastatin should be instead be given other LDL-C Clowering therapy (i.e., a more potent statin that poses a lower risk of myopathy, such as atorvastatin or rosuvastatin)

5 Drugs that contraindicated with any dose of simvastatin Itraconazole Ketoconazole Posaconazole Erythromycin Clarithromycin i Telithromycin HIV protease inhibitors Nefazodone Cyclosporin Danazol Gemfibrozil

6 Do not exceed 10 mg simvastatin daily with Amiodarone Verapamil Diltiazem Do not exceed 20 mg simvastatin daily with Amlodipine Ranolazine Avoid large quantities of grapefruit juice g q g p j (>1 quart daily)

7 Lovastatin label revision (Feb 2012)

8 A 6.7-year, randomized, double-blind trial Comparing the efficacy and safety of 80 mg of simvastatin with those of 20 mg of simvastatin, with or without vitamin B12 and folate Survivors of myocardial infarction

9 Effects of simvastatin dose allocation on first major vascular event

10 Effects of simvastatin dose allocation on myopathy Myopathy-defined as serum CK level l more than 10 times the upper limit of normal with unexplained muscle weakness or pain Simvastatin Simvastatin 20 mg 80 mg (n=6033) (n=6031) 1 patient 52 patients (0.02%) 02%) (0.9%) Rhabdomyolysis-defined as unexplained muscle pain or weakness with a serum CK level more than 40 times the upper limit of normal None 22 patients (0.4%)

11 Talk outline Definition iti Mechanism Statin properties Factor affecting Environment & Genetic factors DDI Management & Monitoring

12 The clinical spectrum of statin-induced myopathy Condition Myopathy Asymptomatic CK elevation Myalgia Myositis Rhabdomyolysis Definition General term to describe all skeletal muscle-related adverse effects CK elevation without muscle symptoms Muscle pain or weakness without CK elevation Muscle symptoms with CK elevation typically <10x ULN Muscle symptoms with CK elevation typically >10x ULN, and with creatinine elevation (usually with brown urine and urinary myoglobin) (Drug Saf 2010; 33: )

13 Observational study of muscular symptoms in an unselected population of 7924 hyperlipidemic pts receiving high-dosage g statin therapy in a usual care, outpatient setting in France The rate of occurrence of muscular symptoms in pts receiving high-dose statin therapy (10.5% ) which is considerably higher than 1-5% reported in clinical trials

14 PRIMO STUDY

15 Possible Mechanism of statininduced myopathy

16 Factors predisposing p statin-induced myopathy Statin Patient Drug-drug properties characteristics interaction Dose Properties Water solubility First-pass metabolism Exercise Demographic Age, race, sex Comorbidities Genetic polymorphism PK interaction CYP OATP1B1 UGT PD interaction Synergic myotoxicity

17 (Accessed on 5 Nov 2011)

18 Physicochemical properties of statins: Lipophilicity & Hydrophilicity Statin Log P Less Rosuvastatin -0.3 Hydrophilicity uptake into muscle cell Pravastatin -0.2 Fluvastatin ti 3.2 Lipophilicity it Pitavastatin 3.5 Atorvastatin 4.1 Lovastatin ti 4.3 Simvastatin 4.7

19 Dose dependent but not related to the degree of LDL C reduction

20 Factors predisposing p statin-induced myopathy Statin Patient Drug-drug properties characteristics interaction Dose Properties Water solubility First-pass metabolism Exercise Demographic Age, race, sex Co-morbidities Genetic polymorphism PK interaction CYP OATP1B1 UGT PD interaction Synergic myotoxicity

21 Pharmacokinetic Drug Interactions First-pass metabolism CYP3A4 A Absorption A Absorption SLCO1B1 (OATP1B1) D Distribution D Di t ib ti Transporter M Metabolism Phase I: CYP 3A4, 2C9 Phase II: UGT E Excretion

22 Pharmacokinetic Drug Interactions A Absorption A Absorption First-pass metabolism CYP3A4 Inhibition of these steps may increase exposure D Distribution SLCO1B1 (OATP1B1) D Di (AUC t ibandti Cmax) of object Transporter drug (statin) and potentiate the risk of myopathy M Metabolism E Excretion Phase I: CYP 3A4, 2C9 Phase II: UGT

23 Inhibitors of enzymatic pathways involved in the metabolism of statins CMRO 2011; 27:

24 Statin PK properties Lva Pva Sva Fva Atv Rsv Ptva Renal excretion (%) <6 < Hepatic and biliary excretion (%) >68 NA Cytochrome P450 First-pass metabolism by CYP3A4 3A4 None 3A4 (>80%) 2C9 (75%) 3A4 2C9/2C 19 (10%) OATP substrate t 2C9 UGT substrate

25 Increase AUC and Cmax of statin

26 Clinical DDI data of CYP3A4 inhibitors and statins metabolized by CYP3A4 Inhibitor Substrate AUC fold increase Cmax fold increase Itraconazole Simvastatin >10 >10 Simvastatin acid Lovastatin >20 >20 Lovastatin acid Atorvastatin Erythromycin Simvastatin acid Atorvastatin Nelfinavir Simvastatin acid Ritonavir+ Saquinavir Atorvastatin Simvastatin acid Atorvastatin

27 Clinical DDI data of CYP3A4 inhibitors and statins metabolized by CYP3A4 Inhibitor Substrate AUC fold increase Cmax fold increase Grapefruit juice Simvastatin Simvastatin acid Lovastatin Lovastatin acid Atorvastatin

28 Clinical DDI data of CYP2C9 inhibitors and statins metabolized by CYP2C9 CYP2C9 Statins Fold Fold inhibitors/ increased increased Substrates of AUC of Cmax Fluconazole Fluvastatin Rosuvastatin Phenytoin Fluvastatin Glibenclamide Fluvastatin Omeprazole Fluvastatin

29 Pharmacokinetic Drug Interactions First-pass metabolism CYP3A4 A Absorption A Absorption SLCO1B1 (OATP1B1) D Distribution D Di t ib ti Transporter M Metabolism Phase I: CYP 3A4, 2C9 Phase II: UGT E Excretion

30 Increased AUC and Cmax of statin ti All statins are substrate of membrane transporter OATP1B1 inhibitors: cyclosporin, saquinavir, ritonavir, lopinavir

31 Effect of cyclosporin on statin exposure Statins Fold Increased of Fold increased of AUC Cmax Simvastatin Atorvastatin Pravastatin Fluvastatin Rosuvastatin Pitavastatin

32 Pharmacokinetic Drug Interactions First-pass metabolism CYP3A4 A Absorption A Absorption SLCO1B1 (OATP1B1) D Distribution D Di t ib ti Transporter M Metabolism Phase I: CYP 3A4, 2C9 Phase II: UGT E Excretion

33 Statin glucuronidation pathway (DMD 2002; 30: ) Gemfibrozil il but not fenofibratefib

34 Effect of gemfibrozil or fenofibrate on statin exposure Cmax AUC Gemfibrozil Fenofibrate Gemfibrozil Fenofibrate Simvastatin 2.1-fold No effect 2.9-fold No effect Pravastatin 1.8-fold No effect 2.0-fold No effect Rosuvastatin 2.2-fold No effect 1.9-fold No effect Fluvastatin No effect No effect No effect No effect Atorvastatint ti Data not No effect Data not No effect available available Diabetes, Obesity and Metabolism 2009; 11:

35 Gemfibrozil Fenofibrate Pharmacodynamic drug interaction Pharmacokinetic None drug interaction Am J Cardiol 2005; 95: 120-2

36 Site of interactions affecting pharmacokinetics of statins Clin Pharm Ther 2006; 80:

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38 Talk outline Definition iti Mechanism Statin properties Factor affecting Environment & Genetic factors DDI Management & Monitoring

39 Monitoring and Surveillance (Am J Cardiol 2006; 97:89C-94C) Routine CK levels in asymptomatic pts is not recommended Baseline CK only in pts at high risk of myopathy If symptomatic, CK levels should be monitored and rule out other etiologies of muscle symptoms

40 Monitoring and Surveillance (Am J Cardiol 2006; 97:89C-94C) In pts with tolerable muscle symptoms and CK<10 x ULN, statin therapy may be continued Regardless to CK level, l discontinue statin ti if symptoms become intolerable In pts who develop rhabdomyolysis (CK>10x ULN with an elevation in SCr or requiring IV hydration), statin therapy should be stopped

41 Monitoring and Surveillance (Am J Cardiol 2006; 97:89C-94C) Rechallenge Re-evaluate LDL goal Evaluate factors potentiate myopathy; i.e. DDI Try same statin ti at lower dose OR other statin (more hydrophilicity) Other options Drug combination

42 Coenzyme Q10 (Ubiquinone) Statin have been shown to reduce plasma/levels of Co-Q10 However, statin treatment does not consistently reduce intramuscular Co-Q10 levels Most studies demonstrate no benefit to Co-Q10 therapy Co-Q10 prophylactic or acute treatment cannot be recommended at this time