Review CDK4/6 Inhibitors in Breast Cancer Treatment: Potential Interactions with Drug, Gene and Pathophysiological Conditions

Rossana Roncato 1,*,†, Jacopo Angelini 2,†, Arianna Pani 2,3,†, Erika Cecchin 1, Andrea Sartore-Bianchi 2,4, Salvatore Siena 2,4, Elena De Mattia 1, Francesco Scaglione 2,3,‡ and Giuseppe Toffoli 1,‡

1 1 Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico (CRO), IRCCS, 33081 Aviano, Italy; [email protected] (E.C.); [email protected] (E.D.M.); [email protected] (G.T.) 2 Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, 20122 Milan, Italy; [email protected] (J.A.); [email protected] (A.P.); [email protected] (A.S-B.); [email protected] (S.S.); [email protected] (F.S.) 3 Clinical Pharmacology Unit, ASST Grande Ospedale Metropolitano Niguarda, Piazza dell'Ospedale Maggiore 3, 20162 Milan, Italy 4 Department of Hematology and Oncology, Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20162 Milan, Italy * Correspondence: [email protected]; Tel.:+390434659130 † These authors contributed equally. ‡ These authors share senior authorship.

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Table S1. Co-administered agents categorized according to their potential risk for Drug-Drug interaction (DDI) in combination with CDK4/6 inhibitors (CDKis). Colors suggest the risk of DDI with CDKis: green, low risk DDI; orange, moderate risk DDI; red, high risk DDI. ADME, absorption, distribution, metabolism, and excretion; GI, Gastrointestinal; TdP, Torsades de Pointes; NTI, narrow therapeutic index. * Cardiological toxicity should be considered especially for ribociclib due to the QT prolongation. Modified table from Bellet et al. 2019 [50].

Non ADME DDI (TdP) ADME DDI with Effect of CDKis on Co-administered agent Co-administered agents (Caution Should Be Palbociclib, Ribociclib and Co-Administered (Class) (Name) Exercised in Combination Abemaciclib Agents with Ribociclib *) Beta-lactams; Tetracyclines; Fosfomycin; Linezolid; Clindamycin; Glycopeptides; Low risk DDI Low risk DDI - Aminoglucosides, Daptomycin. Trimethoprim major Trimethoprim major CYP3A4 substrate; CYP3A4 substrate; Ribociclib can Trimetoprim/sulfamethoxazole; Azithromycin, levofloxacin Azithromycin, levofloxacin increase Macrolides (azithromycin); and moxifloxacin known and moxifloxacin known concentration of Fluoroquinolones (levofloxacin, Antibiotics TdP risk; Norfloxacin and TdP risk; Norfloxacin and trimethoprim, with moxifloxacin, norfloxacin, ofloxacin); ofloxacin possible TdP risk; ofloxacin possible TdP risk; bone marrow Metronidazole Metronidazole conditional Metronidazole conditional toxicity TdP risk TdP risk Moderate to strong CYP3A4 Moderate to strong CYP3A4 Macrolides (erythromycin, inhibitors/inducers (quasi- inhibitors/inducers (quasi- High risk DDI (major claritrhromycin); Rifampicin; irreversible inhibition for irreversible inhibition for CYP3A4 substrate) Anti-infective Fluoroquinolones (ciprofloxacin) macrolides) macrolides) Acyclovir, famciclovir, valacyclovir, Antiherpetic Low risk DDI Low risk DDI - brivudine, ganciclovir, valganciclovir Flu Oseltamivir Low risk DDI Low risk DDI - Nucleoside analog reverse transcriptase inhibitors (lamivudine, abacavir, Low risk DDI Low risk DDI - tenofivir) Integrase inhibitors (dolutegravir, raltegravir) Non-nucleoside reverse transcriptase Major substrate and weak Major substrate and weak Major CYP3A4 HIV, hepatitis inhibitors: nevirapine CYP3A4 inducer CYP3A4 inducer substrate Protease inhibitors for HIV and HCV High risk DDI (atazanavir, darunavir, lopinavir, Moderate to strong CYP3A4 Moderate to strong CYP3A4 (Major CYP3A4 indinavir, ritonavir (usually inhibitors/inducers inhibitors/inducers substrate) administered in combination with

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ritonavir); Non-nucleoside reverse transcriptase inhibitors: efavirenz Amphotericin B with conditional TdP risk, Amphotericin B Low risk DDI caution should be exercised Low risk DDI in combination with ribociclib. Antifungal Echinocandins (caspofungin, Low risk DDI Low risk DDI - anidulafungin, micafungin) Fluconazole, itraconazole, isavuconazole, High risk DDI Moderate to strong CYP3A4 Moderate to strong CYP3A4 posaconazole, voriconazole, (Major CYP3A4 inhibitors inhibitors ketoconazole substrate) Metoclopramide, olanzapine, Conditional to possible TdP Low risk DDI Low risk DDI palonosetron, granisetron risk Weak CYP3A4 Weak CYP3A4 Rolapitant, fosaprepitant, Antiemetics inducer/inhibitor of inducer/inhibitor of Major substrates dexamethasone CYP3A4 CYP3A4 Aprepitant, netupitant, ondansetron, Moderate CYP3A4 Moderate CYP3A4 inhibitor Major substrates domperidone inhibitor. Ranitidine, famotidine, alluminium hydroxide, bismuth subsalicylate, zinc Low risk DDI Low risk DDI - Antacids and acexamate, sucralfate gastric mucosal Esomeprazole, omeprazole, pantoprazole Low risk DDI Conditional TdP risk Low risk DDI protective High risk DDI (major GI treatment Lansoprazole, rabeprazole - Conditional TdP risk CYP3A4 substrate) Low risk DDI with Antidiarrheals Racecadotril, loperamide Low risk DDI racecadotril. loperamide Low risk DDI has conditional TdP risk Lactulose, macrogol, magnesium Low risk DDI Low risk DDI - Prokinetics and hydroxide, scopolamine-butylbromide laxative High risk DDI (major Cinitapride, naloxegol - - CYP3A4 substrate) Dexchlorpheniramine, cetirizine, Low risk DDI Low risk DDI - loratadine, desloratadine, fexofenadine Antihistamines Conditional to possible TdP Diphenhydramine, promethazine Low risk DDI Low risk DDI risk

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High risk DDI (major Ebastine, rupatadine - - CYP3A4 substrate) All Low risk DDI Low risk DDI High risk DDI (major Sartans Losartan - - CYP3A4 substrate). Losartan: NTI Enalapril, captopril, fosinopril, ramipril, ACE inhibitors Low risk DDI Low risk DDI - quinapril All Low risk DDI Low risk DDI - High risk DDI (major Beta blockers Bisoprolol - - CYP3A4 substrate). Bisoprolol: NTI Clevidipine Low risk DDI Low risk DDI - High risk DDI (major CYP3A4 substrate). Hypertension and Nifedipine and congestive heart All dihydropyridines - - nicardipine failure treatment Calcium channel moderate CYP3A4 blockers inhibitors. High risk DDI (major Non dihydropyridines (verapamil, CYP3A4 substrate). - - diltiazem) Verapamil moderate CYP3A4 inhibitor Loop diuretics (furosemide, torsemide, Low risk DDI Conditional TdP risk Low risk DDI hydrochlorothiazide, indapamide) Potassium sparing diuretics (amiloride, Low risk DDI Low risk DDI - Diuretics triamterene, spironolactone) High risk DDI Potassium sparing diuretics (eplerenone) - - (major/sensitive CYP3A4 substrate) Glicazide, glibenclamide, glisentide, Sulfonylureas Low risk DDI Low risk DDI - glipizide, gliquidone Alpha Glucose-lowering glycosidase Acarbose, miglitol Low risk DDI Low risk DDI - treatment inhibitors Albiglutide, dulaglutide, exenatide, GLP-1 Low risk DDI Low risk DDI - liraglutide, lixisenatide

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Vildagliptin, alogliptin, sitagliptin Low risk DDI Low risk DDI - DPP-4 inhibitors High risk DDI (major Saxagliptin, linagliptin - - CYP3A4 substrate) SGLT2 Canagliflozin, dapagliflozin Low risk DDI Low risk DDI - inhibitors Risk of competition Biguanides Metformin - - for the membrane transporters High risk DDI (major Metglinides Repaglinide - - CYP3A4 substrate) Pitavastatin Low risk DDI Low risk DDI - Unknown risk of QT Fluvastatin, pravastatin, rosuvastatin - - prolongation High risk DDI (major Lipid-lowering Statins CYP3A4 substrate). treatment Both simvastatin and Simvastatin, atorvastatin - - atorvastatin are sensitive and moderate-sensitive Fibrates All Low risk DDI Low risk DDI - COX-1 ASA, triflusal Low risk DDI Low risk DDI - inhibitors Dipyridamole Low risk DDI Low risk DDI - PDE-3 inhibitors Weak CYP3A4 inhibitor of High risk DDI (major Clilostazol - CYP3A4 CYP3A4 substrate) High risk DDI (major Ticagrelor is a weak CYP3A4 substrate). Ticlopidine, ticagrelor, prasugrel - P2Y antagonists inhibitor of CYP3A4 Ticagrelor: Antiplatelet sensitive/NTI Clopidogrel Low risk DDI Low risk DDI - GP IIb/IIIa Abciximab, eptifibatide, tirofiban Low risk DDI Low risk DDI - antagonists Selective IP Prostacyclin P-gp, BCRP substrate. Selexipag - - Receptor Minor CYP3A4 substrate Agonist PGI2 analogue Iloprost, epoprostenol sodium Low risk DDI Low risk DDI -

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Coumarin Warfarin, acenocoumarol Low risk DDI Low risk DDI - Heparin Heparin and LMWH Low risk DDI Low risk DDI - Bivalirudina Low risk DDI Low risk DDI - DOACs FIIa Unknown risk of QT inhibitors Dabigatran - prolongation (under P-gp substrate review) P-gp substrate. Minor Edoxaban - - Anticoagulant CYP3A4 substrate High risk DDI (major CYP3A4 substrate). DOACs Fxa P-gp and BCRP inhibitors Apixaban, rivaroxaban - - substrates. Rivaroxaban: moderate-sensitive substrate All Low risk DDI Low risk DDI - Major CYP3A4 Parecoxib - - substrate. Non-opioid High risk DDI (major Ergotamine and dihydro-ergotamine - - CYP3A4 substrate). Ergotamine: NTI Morphine, hydromorphone, tapentadol, Low risk DDI Low risk DDI - Analgesics Codeine Possible for tramadol and Major CYP3A4 Tramadol, buprenorphine, oxycodon - buprenorphine substrate Opioid High risk DDI (major CYP3A4 substrate). Known TdP risk for methadone, fentanyl - Fentanyl: NTI. methadone Consider dose adjustment Pregabalin, gabapentin, levetiracetam, lamotrigine, topiramate, baclofen, - Low risk DDI Low risk DDI - clonidine, octreotide, alendronate, Anticonvulsivants zoledronate, denosumab and Adjuvants Lacosamide, valproic acid, prednisone, - methylprednisolone, hydrocortisone, Low risk DDI Low risk DDI - fextromethorphan

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Dexamethasone and Except Dexamethasone, zonisamide, - Oxacarazepine are weak Conditional TdP risk oxcarbazepine major oxcarbazepine, ketamine CYP3A4 inducers CYP3A4 substrate. Carbamazepine and phenytoin are Carbamazepine, phenobarbital, Conditional to known TdP substrates of - Strong CYP3A4 inducers phenytoin risk CYP3A4, respectively major and minor - Duloxetine, desvenlafaxine, vortioxetine Low risk DDI Low risk DDI - - Paroxetine, sertraline, fluoxetine - Conditional TdP risk. - High risk DDI (major Antidepressants Trazodone, mirtazapine, venlafaxine, CYP3A4 substrate). - - - citalopram, escitalopram Citalopram and escitalopram: NTI Conditional to possible TdP - Olanzapine, amisulpride Low risk DDI risk. However, the risk is - dose dependent High risk DDI. Paliperidone, risperidone, asenapine, Conditional to possible TdP Quetiapine: major - - Antipsychotic perphenazine, clozapine, quetiapine risk CYP34 substrate and NTI High risk DDI. Sulpiride, chlorpromazine, Ziprasidone moderate Conditional to known TdP Pimozide: major - levopìmepromazine, ziprasidone, CYP3A4 inhibitor. risk CYP34 substrate and aripiprazole, haloperidol, pimozide NTI Lorazepam, lormetazepam, clotiazepam, Low risk DDI. Clobazapam - Low risk DDI - bromazepam, clobazam weak CYP3A4 inducer Anxiolytics and Diazepam, clorazepate, clonazepam, hypnotics Alprazolam weak CYP3A4 - midazolam, flurazepam, alprazolam, - - inhibitor zolpidem, zopiclone