Prof. Alberto Corsini Università degli Studi di Milano Statine, integratori a base di rosso fermentato e rischio di interazioni farmacologiche Prof. Alberto Corsini Università degli Studi di Milano

Outline of the presentation Statine Integratori a base di riso rosso fermentato

FDA Reports of Rhabdomyolysis, January 1, 1990–March 31, 2002 Due to Drug, % Outcomes, %* No. of Reports Drugs Death Hospitalization Cerivastatin Simvastatin Atorvastatin Pravastatin Lovastatin Fluvastatin Total 1899 612 383 243 147 55 3339 56.9 18.3 11.5 7.3 4.4 1.6 100.0 7.2 8.0 9.5 7.9 10.9 4.6 7.8 56.7 51.5 45.1 58.5 50.3 49.4 53.6

58% OF CASES WERE ASSOCIATED WITH CONCOMITANT MEDICATIONS AFFECTING STATIN METABOLISM MIBEFRADIL 2% FIBRATES 38% CYCLOSPORINE 4% MACROLIDE ANTIBIOTICS 3% WARFARIN DIGOXIN 5% AZOLE ANTIFUNGALS 1% Paul D. Thompson, et al, JAMA 2003;289:1681-1690

Drugs LESCOL LESCOL, ADALAT COVERSYL, ZYLORIC, LESCOL NORVASC, LESCOL XL LESCOL, LOPID, BAYCOL VIOXX, LESCOL ASPIRIN, LOPID, BAYCOL, LESCOL, RANITIDINE HYDROCHLORIDE, DILTIAZEM HYDROCHLORIDE, ATENOLOL, ISORDIL, LANOXIN, GLYBURIDE, LASIX, LOTENSIN COUMADIN, ALLOPURINOL, GEMFIBROZIL, CARDIZEM, LANOXIN, PROPRANOLOL HYDROCHLORIDE, LESCOL, REZULIN CALCITONIN-SALMON, FLUVASTATIN, GEMFIBROZIL, DEVARON, SINTROM, CAPTOPRIL, SIMVASTATIN, LIPOBAY BAYCOL, ASPIRIN, LOPID, TAGAMET, NORVASC, LESCOL, CLARITIN, ALTACE, HYTRIN, TOPROL-XL LOPID, LESCOL, BAYCOL FLUVASTATIN SODIUM, METOPROLOL TARTRATE, CERIVASTATIN SODIUM, GEMFIBROZIL, RANITIDINE HYDROCHLORIDE, TRIAMTERENE + HYDROCHLOROTHIAZIDE MAGNESIUM OXIDE, LENDORMIN, FAMOTIDINE, JUVELA NICOTINATE, DEPAS, LOCOL, GASMOTIN, MARZULENE S, MEVALOTIN, FURSULTIAMINE LESCOL, ATENOLOL, ASPIRIN, HYDROCHLOROTHIAZIDE, LOTREL, DYAZIDE, LORAZEPAM, MEDROL LESCOL, ATENOLOL, METICORTEN, LEVOTHYROXINE SODIUM, NATRILIX BAYCOL, LESCOL, GLYBURIDE, GLUCOPHAGE, PRANDIN Dati FDA 2011

Interazioni farmacodinamiche sono quelle in cui gli effetti di un farmaco vengono influenzati dalla presenza al sito d’azione di un altro farmaco Interazioni farmacocinetiche sono quelle che possono influenzare i processi con i quali i farmaci vengono assorbiti, distribuiti, metabolizzati ed eliminati (ADME)

Structural Formulas of HMG-CoA and of some Type 1 and Type 2 Statins ES Istvan, J Deisenhofer Science 2001; 292: 1160-1164

Statins Pharmacokinetic Properties Fermentation-Derived Synthetic Proprietà Simvastatin Lovastatin Pravastatin Fluvastatin Atorvastatin Cerivastatin Rosuvastatin Absorption (%) 60 30 34 >90 3 >98 50 Bioavailability (%) 5 5 20 30 12 60 20 Half-life (hr) 2 2,9 1-3 1 14 2-3 20.8 Protein Binding (%) 95 >95 50 >98 >98 >99 88 Metabolic Clearance CYP3A4 CYP3A4 multiple CYP2C9 CYP3A4 CYP3A4 biliar (incl. CYP3A4) (CYP2C9,2C19 minima) 1. Physician’s Desk Reference (PDR), 52nd ed., 1998 2. Christians, Pharmacol. Ther 1998;80 (1):1-34 3. Muck, 11th Int’l Symposium on Atherosclerosis, Paris, October 1997 26

Clinically Relevant Drug Interactions with Statins + = interaction reported; - = no interaction reported Ballantyne CM, Corsini A et al. 2003, Arch Intern Med

Human Cytochrome P450 Isoenzymes Known to Oxidize Clinically Used Drugs CYP2C9 CYP2C19 CYP2D6 CYP3A4 Alprenolol Diclofenac Fluvastatin Hexobarbital N- desmethyldiazepan Tolbutamide Warfarin Rosuvastatin Pitavastatin (also CYP2C8) Diazepan Ibobrufen Mephenytoin Methylphenobarbital Omeprazol Proguanyl Phenytoin Amitriptyline Bufaralol Codeine Debrisoquine Dextromethorphan Encainide Flecainide Imipramine Metoprolol Mibefradil Nortriptyline Perhexiline Perphenazine Propafenone Propanolol Sparteine Thioridazine Timolol Amiodarone Atorvastatin Cerivastatin Clarithromycin Cyclosporine A Diltiazem Erythromycin Ketoconazole Itraconazole Lovastatin MIbefradil l Midazolam Nefazodone Nifedipine Protease inhibitors Quinidine Sildefanil Simvastatin Terbinafine Verapamil Modified from: Brower et al., In: Evans W.E. (Ed). Applied Pharmacokinetics. Principles of Therapeutic Drug Monitoring, 3rd ed., 1992

L’inibizione enzimatica in genere coinvolge Molte interazioni tra farmaci sono la conseguenza dell’inibizione o dell’induzione dei Citocromi CYP450 responsabili del metabolismo di più della metà dei farmaci correntemente a disposizione L’inibizione enzimatica in genere coinvolge la competizione di un altro farmaco per lo stesso sito di legame dell’enzima L’induzione enzimatica si verifica quando un farmaco è in grado di stimolare la sintesi proteica enzimatica, aumentando così la capacità di metabolizzazione dell’enzima

Human Hepatic P450 Enzymes with Model Inhibitors and Inducers Cyclosporine A Erythromycin Ketoconazole INHIBITORS Tetrahydro- furane Fluconazole Sulphaphenazole Fluvoxamine Quinidine Methoxsalen CYP3A4/5/7 ~ 30% CYP2C19 < 10% CYP2C8/9/18 ~ 20% CYP1A2 ~ 15% CYP2E1 ~ 10% CYP 2B6 CYP2A6 < 5% CYP2D6 < 5% CYP 1A1 Phenobarbital No known Omeprazol Tobacco smoke Phenobarbital Rifampicin Phenobarbital Rifampicin Ethanol Isoniazid Carbamazepine Dexamethasone Phenobarbital Phenytoin Rifampicin INDUCERS % = relative amount in human liver Modified from Pelkonen and Breimer 1994 Xenobiotica 28: 1203-1253

Bellosta S, Corsini A. Expert Opin Drug Saf. 2018 Jan;17(1):25-37

Interaction between a statin and a CYP substrate/inhibitor Bellosta S, Corsini A Expert Opin Drug Saf. 2018 Jan;17(1):25-37

Simvastatin acid (ng/ml) Simvastatin (ng/ml) Concentrazione di simvastatina e di simvastatina acido nel siero dopo co-somministrazione di verapamil () ed eritromicina () Simvastatin acid (ng/ml) Kantola T, et al. Clin Pharmacol Ther 1998; 64:177-82

Alberico L. Catapano et al. Eur Heart J 2016;eurheartj.ehw272

Bellosta S, Corsini A. Expert Opin Drug Saf. 2018 Jan;17(1):25-37 Selected Drugs That May Increase Risk of Myopathy and Rhabdomyolysis When Used Concomitantly With Statins Bellosta S, Corsini A. Expert Opin Drug Saf. 2018 Jan;17(1):25-37

Human Cytochrome P450 Isoenzymes Known to Oxidize Clinically Used Drugs CYP2C9 CYP2C19 CYP2D6 CYP3A4 Alprenolol Diclofenac Fluvastatin Hexobarbital N- desmethyldiazepan Tolbutamide Warfarin Rosuvastatin Pitavastatin (also CYP2C8) Diazepan Ibobrufen Mephenytoin Methylphenobarbital Omeprazol Proguanyl Phenytoin Amitriptyline Bufaralol Codeine Debrisoquine Dextromethorphan Encainide Flecainide Imipramine Metoprolol Mibefradil Nortriptyline Perhexiline Perphenazine Propafenone Propanolol Sparteine Thioridazine Timolol Amiodarone Atorvastatin Cerivastatin Clarithromycin Cyclosporine A Diltiazem Erythromycin Ketoconazole Itraconazole Lovastatin MIbefradil l Midazolam Nefazodone Nifedipine Protease inhibitors Quinidine Sildefanil Simvastatin Terbinafine Verapamil Modified from: Brower et al., In: Evans W.E. (Ed). Applied Pharmacokinetics. Principles of Therapeutic Drug Monitoring, 3rd ed., 1992

Effetto della co-somministrazione di ciclosporina sui parametri farmacocinetici delle statine AUC* Cmax* Cerivastatin  x 3.7  x 4.8 Fluvastatin  x 1.9  x 1.3 Lovastatin  x 20 – Pravastatin  x 5–23  x 8 Simvastatin  x 3–8 – Atorvastatin  x 6  x 6  x 10.6 Rosuvastatin  x 7 *Values shown are the changes relative to the statin alone. AUC, area under the plasma concentration-time curve; Cmax, maximum plasma concentration Corsini A. Cardiovascular Drugs and Therapy 2003; 17:257-277

Interactions Between Statins and Protease Inhibitors Co-administration with PIs Lovastatin, simvastatin Not recommended with protease inhibitors Fluvastatin No significant interactions reported UUse cautiously; start with lowest dose Atorvastatin NNo significant P450 interactions reported; levels increased modestly when used with ritonavir/saquinavir Pravastatin   Corsini A. Cardiovascular Drugs and Therapy 2003; 17:257-277

HIV-drug interaction database of the University of Liverpool. Alberico L. Catapano et al. Eur Heart J 2016;eurheartj.ehw272

Matilda F and Moses SF Expert Opin. Drug Saf. [Early Online] 2012

Effect of Grapefruit Juice on Serum Concentrations of Lovastatin Single oral dose of 80 mg lovastatin. 200 ml double-strenght grapefruit juice, three times a day for 2 days. 10 healthy volunteers. From Kantola T et al. 1998 Clin Pharmacol Ther 63: 397-402

Grapefruit and Statins Daily consumption of a glass of regular-strenght grapefruit juice has a minimal effect on plasma concentrations of lovastatin (about 30% to 40% increase) after a 40 mg evening dose of lovastatin. Rogers JD et al. 1999 Clin Pharmacol Ther 66: 358-366

The effect of CYP and/or membrane transporter inhibitors and inducers on statin pharmacokinetics Neuvonen PJ Cur Op Invest Drugs 11:323-332, 2010

L’inibizione enzimatica in genere coinvolge Molte interazioni tra farmaci sono la conseguenza dell’inibizione o dell’induzione dei Citocromi CYP 450 responsabili del metabolismo di più della metà dei farmaci correntemente a disposizione L’inibizione enzimatica in genere coinvolge la competizione di un altro farmaco per lo stesso sito di legame dell’enzima L’induzione enzimatica si verifica quando un farmaco è in grado di stimolare la sintesi proteica enzimatica, aumentando così la capacità di metabolizzazione dell’enzima

Sostanze con effetto inducente P-INDUTTORE Aumento della trascrizione dell’RNA nucleare DNA Nucleo mRNA sintesi proteica Stabilizzazione dell’RNA messaggero Citocromo P450 IAI Reticolo endoplasmatico Metabolismo del ligando

Concentrazioni plasmatiche di simvastatina in 10 soggetti sani 40 mg di simvastatina in seguito a pretrattamento per 5 giorni con placebo o 600 mg di rifampicina Con placebo Simvastatina (ng/ml) Con rifampicina Tempo (ore) C. Kyrklund et al., Clin Pharmacol Ther 2000; 68:592-7

Bellosta S, Corsini A Expert Opin Drug Saf. 2018 Jan;17(1):25-37

Outline of the presentation Statine Integratori a base di riso rosso fermentato

Il Riso Rosso E’ il prodotto della fermentazione del riso per opera del Monascus purpureus, un micete. Il M. purpureus produce diverse molecole tra cui un pigmento rosso, sostanze batteriostatiche, steroli, acidi grassi mono- e poli-insaturi e le monacoline (0.2%). Le monacoline competono strutturalmente a livello della HMGCoA reduttasi con l’HMGCoA, precursore del mevalonato, inibendo la sintesi del colesterolo e riducendo la colesterolemia LDL attraverso un aumento della sintesi di recettori per le LDL. La monacolina K è chimicamente indistinguibile dalla Lovastatina.

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Nutrafoods (2015) 14:197-205

Nutrafoods (2015) 14:197-205 Nutrafoods (2015) 14:197-205

Lievito rosso: meccanismo d’azione HMG-CoA Reduttasi ↓3-idrossi-3-metilglutaril-CoA ↓ Acido Mevalonico ↓ Colesterolo Acetil-CoA Lieivito rosso (monacoline) Jianping L et al Chinese Medicine, 2006; 1 (4)/Heber D et al Am J Clin Nutr, 1999; 69; 231-236

Liu J et al Chinese Medicine 2006, 1:4 A clinically relevant hypocholesterolaemic effect is observed with RYR preparations providing a daily dose of 2.5–10 mg monacolin K Net benefit of RYR preparations in lipid profile in placebo-controlled trials Liu J et al Chinese Medicine 2006, 1:4

Clinical Pharmacokinetics of Statins Absorption Adapted from Corsini et al. 1999 Pharmacol Ther 84: 413-428 Circulation Supp lIII:50-57, 2004

International Journal of Pharmaceutics 444 (2013) 18– 24 Plasma levels of lovastatin in healthy subjects after a single dose of RYR product (20 mg) or lovastatin tablet in the fasted state International Journal of Pharmaceutics 444 (2013) 18– 24

Statins Pharmacokinetic Properties Fermentation-Derived Synthetic Proprietà Simvastatin Lovastatin Pravastatin Fluvastatin Atorvastatin Cerivastatin Rosuvastatin Absorption (%) 60 30 34 >90 3 >98 50 Bioavailability (%) 5 5 20 30 12 60 20 Half-life (hr) 2 2,9 1-3 1 14 2-3 20.8 Protein Binding (%) 95 >95 50 >98 >98 >99 88 Metabolic Clearance CYP3A4 CYP3A4 multiple CYP2C9 CYP3A4 CYP3A4 biliar (incl. CYP3A4) (CYP2C9,2C19 minima) 1. Physician’s Desk Reference (PDR), 52nd ed., 1998 2. Christians, Pharmacol. Ther 1998;80 (1):1-34 3. Muck, 11th Int’l Symposium on Atherosclerosis, Paris, October 1997 26

Lovastatina RCP

Alberico L. Catapano et al. Eur Heart J 2016;eurheartj.ehw272 Transplantation. 2002 Oct 27;74(8):1200-1 19 September 2006 Annals of Internal Medicine Volume 145 • Number 6 Alberico L. Catapano et al. Eur Heart J 2016;eurheartj.ehw272

Effetti collaterali da RYR (Monascus) in Italia 52 reports (su 55 AR) relativi al RYR raccolti tra aprile 2002 e settembre 2015 13 ospedalizzazioni; tutti risolti positivamente Una Rabdomiolisi, 10 casi di danno epatico, 19 casi di mialgia e/o aumento CK Mazzanti G et al, Brit J Clin Pharm, 2017

Effetti collaterali da RYR (Monascus) in Italia 52 reports (su 55 AR) relativi al RYR raccolti tra aprile 2002 e settembre 2015 13 ospedalizzazioni; tutti risolti positivamente Una Rabdomiolisi*, 10 casi di danno epatico, 19 casi di mialgia e/o aumento CK * In un paziente con pregressa rabdomiolisi da statina! Mazzanti G et al, Brit J Clin Pharm, 2017

Vantaggi e svantaggi degli estratti di riso rosso con azione ipocolesterolemizzante Abbiamo rivisto la letteratura che riguardava l’utilizzo dei prinicipali nutraceutci ed abbiamo definito l’entità della riduzione del colesterolo che è possibile ottenere. Position statement SISA/SID on Nutraceuticals for the treatment of hypercholesterolemia Giornale Italiano dell’Arteriosclerosi 2016; 7 (2): 3-30

Take home message Pharmacokinetic DDI can influence drug efficacy, tolerability and compliance of statins, and such interactions are both common and of more clinical relevance than often appreciated Even well-characterized statin DDI continue not to be considered adequately by physicians in their prescribing decisions, Strategies to reduce DDI with potential adverse effects should be targeted at prescribers and pharmacists.

Take home message (con’t) Polypharmacy, which includes not only prescribed medications, but also other self-prescribed or OTC medications (including vitamins, minerals and herbal remedies and foodstuffs) are a potential causes of DDI with statins Special populations at high risk of CVD, such as patients with coronary heart disease, dyslipidemia, diabetes, hypertension, nephrotic disease, HIV, organ transplant patients, women and the elderly, deserve particular attention to avoid clinically relevant DDI