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Tyrosine kinases inhibitors (TKI) are small molecules that interfere with cell signalling and target selected malignancies. The concern associated with oral drugs is related to their low and unpredictable bioavailability. In the past years, several TKI have been introduced in oncology and the risk of serious drug-drug interactions is very important and deserves to be taken into consideration. It is difficult to find a concise tool to help oncologists with this matter and this could create issues in the daily clinic. This article gives a brief overview of known or suspected interactions either with other drugs or foods. Oncologists should carefully review the concomitant medications for each patient in order to prevent any relevant interactions or to monitor them closely.Â
Tyrosine kinases inhibitors (TKI) are small molecules, orally administered that interfere with cell signalling and allow target-specific treatment for selected malignancies. Patientsâ preference for oral treatment is well known and from the medical perspective, although it could be perceived as an advantage, the concern is that oral drugs may have low and unpredictable bioavailability. This could be due to variable degradation in gastrointestinal system, intestinal P-glycoprotein and interaction with cytochrome P450 (CYP3A4) catalytic activity which varies as much as 10-fold among individuals. In the past years, several TKI have been introduced in oncology. These agents are currently extensively used and serious drug-drug interactions are a high risk event. This article gives a brief overview of known or suspected drug-drug interactions between TKI and other drugs. Most interactions are related to metabolism by cytochrome P450 isoenzymes, altered stomach pH and prolongation of the QTc interval. The data are presented in tables. Oncologists should carefully review the concomitant medications for each patient in order to prevent any relevant interactions or to monitor closely them. Â
Table 1: Cytochrome P450, family 3, subfamily A (CYP3A4/5) inhibitors and inducers inhibitors   may increase plasma concentrations  inducers   may reduce plasma concentrations  strong  Ketoconazole Itraconazole Voriconazole  Avoid concomitant use or dose adjustment or monitoring strong  Rifampicin Rifabutin Rifapentin Avoid concomitant use or dose adjustment or monitoring  Clarithromycin  Dexamethasone  Atazanavir Indinavir Nefazodone Nelfinavir Ritonavir Saquinavir  Phenytoin Carbamazepine Phenobarbital Topiramate  Nefazodone  Hypericum perforatum [St. John's wort]) Moderate  Diltiazem Verapamil Amiodarone  Unspecified potency  Modafinil   Aprepitant  Capsaicin  Bicalutamide  Pioglitazone Troglitazone  Erythromycin    Grapefruit    Valerian   Weak  Valproic  Â
Table 2: Drugs which prolong QT interval  Antisickness Onsansetron Domperidone  Antidepressants Fluoxetine Trazodone Citalopram   Antiarrhythmics Flecainide Quinidine Procainamide Sotalol Amiodarone  Antifungal Fluconazole Voriconazole Hormonal therapy Gosereline Opioids Methadone B2 agonists Salmeterol Alpha-blockers Alfuzosin   Antibiotics Azithromycin Ciprofloxacin Clarithromycin Erythromycin  Antipsychotics Chlorpromazine Haloperidol  Antimalarial Chloroquine Quinine
Table 3: CYP3A substrates Antifungals Ketoconazole Itraconazole Antibiotics Clarithromycin Erythromycin  Antidepressants Mirtazapine Venlafaxine Trazodone Sertraline Citalopram Norfluoxetine Amitryptiline Antipsychotics Haloperidol Opioids Buprenorphine Codeine Fentanyl Methadone Tramadol Alfentanil Benzodiazepines and hypnotics zopiclone alprazolam zolpidem midazolam diazepam Statins Atorvastatin Simvastatin Calcium chanel blockers nifedipine Diltiazem Verapamil Antiemetics aprepitant Domperidone ondansetron Steroids dexamethasone hydrocortisone Proton pump inhibitor Omeprazole Antiplatelets Clopidogrel Beta agonists Salmeterol Stimulants Caffeine Protease inhibitors Indinavir Ritonavir H1 receptor antagonists Chlorphenamine PDE5 inhibitors Sildenafil antiarrhythmics Amiodarone
Table 4: Drugs and P-glycoprotein (PgP) Substrates Inhibitors Inducers Colchicine Verapamil Carbamazepine Digoxin Amiodarone Rifampicin Morphine Clarithromycin St Johnâs Wort Indinavir Erythromycin   Ketoconazole   Quinidine Â
Table 5: Drugs interacting with CYP3A substrates  CYP3A substrates Crizotinib Dabrafenib Lenvatinib Imatinib  Table 6: Drug interactions with CYP3A inhibitors/inducers Axitinib  CYP3A4/5 inducers       CYP3A4/5 inhibitors       Prolong QT interval  Cabozantinib Crizotinib Crizotinib Everolimus  Gefitinib Imatinib Lapatinib Lapatinib Pazopanib  Sorafenib Sorafenib Sunitinib Sunitinib Regorafenib  Vemurafenib   Vandetanib  Table 7: Drugs interacting with PgP substrates  PgP substrates Lapatinib Lenvatinib Sorafenib
Table 8: Interactions with pump inhibitors and antiacids Antiacids Increase levels of TKI Reduce levels of TKI Observations Omeprazole  Axitinib Crizotinib  Gefitinib Lapatinib If taken regularly Pazopanib To take 1 hour before or 2 h after quick antiacids and 2 h before or 10 h after antiH2  Ranitidine  Pazopanib  Others  Pazopanib Dabrafenib  Trametinib
Table 9: Interactions with anticoagulants  Warfarin Option Axitinib no interaction  Cabozantinib no interaction   Crizotinib no interaction   Dabrafenib Reduce warfarin exposure Close monitoring Gefitinib Increase risk of bleeding Close monitoring Everolimus no interaction   Imatinib Not to use Low molecular weight heparin Lenvatinib no interaction   Lapatinib no interaction   Regorafenib Increase risk of bleeding Close monitoring Sorafenib Low risk  Sunitinib no interaction   Pazopanib no interaction   Vandetanib Possible interaction Close monitoring Not to use dabigatran Vemurafenib Increase risk of bleeding Close monitoring
Table 10: Other interactions  Increase Decrease No significant change Levels of midazolam Crizotinib Vemurafenib Regorafenib  Everolimus  Sorafenib Lapatinib  Pazopanib  Levels of oral contraception  Vemurafenib Lenvatinib??   Levels of statins Imatinib  Everolimus Atorvastatin Regorafenib  Simvastatin Pazopanib  Bisphosphonates Cabozantinib   Sunitinib  Metformin Vandetanib    Digoxin Crizotinib  Regorafenib  Lapatinib Sorafenib Vandetanib Vemurafenib  Dextromethorphan Pazopanib  Sorafenib
Table 11: Method of administration  As a whole With food Without food Water Other options Axitinib X X X X  Cabozantinib X  X X 2 h before and 1 h after Crizotinib X X X X  Dabrafenib X   X 1 h before or 2 after a meal Gefitinib X   X Dissolve in half glass of water (20 min), drink immediately. Add more water and drink Everolimus X X X X  Imatinib X X  X  Lenvatinib    X/apple juice In 1 tablespoon for 10 min, stir for 3 min and drink Lapatinib X  X  1 h before or after a meal Regorafenib X X Low fat  X  Sorafenib X X Low fat X  X  Sunitinib X X X X  Pazopanib X  X  1 h before or 2 h after Trametinib X   X 1 h before or 2 after a meal Vandetanib X  X X disperse in half glass of water Before or after a meal Vemurafenib X    X Â
In the past decade, many TKI have been introduced in oncology as targeted therapies against different malignancies. Although they seem to be well tolerated, the risk of serious interactions exists and it is the oncologist's responsibility to know these in order to prevent any relevant issues, such as toxicities or lack of effectiveness due to reduced bioavailability. This brief summary presented in Tables form, pretends to be an easy tool to consult in the routine practice to help doctors make quick decisions and manage correctly these medications.
I thank all those who have always challenged me; I appreciate their effort to make me brave enough to stand up for myself