Original Articles
 

By Dr. Esther Una Cidon
Corresponding Author Dr. Esther Una Cidon
Oncology Department, Royal Bournemouth Hospital, Castle Lane East - United Kingdom BH7 7DW
Submitting Author Dr. Esther Una Cidon
ONCOLOGY

Tyrosine Kinase inhibitors, targeted therapy, cytochrome, bioavailability, interactions, QTc interval

Una Cidon E. Tyrosine kinases inhibitors: interactions and safe use. WebmedCentral ONCOLOGY 2017;8(6):WMC005308

This is an open-access article distributed under the terms of the Creative Commons Attribution License(CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Submitted on: 01 Jun 2017 10:25:38 PM GMT
Published on: 05 Jun 2017 09:36:32 AM GMT

Abstract


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. 

Introduction


Tyrosine kinases inhibitors (TKI) are small molecules, orally administered that interfere with cell signalling and allow target-specific treatment for selected malignancies. Patients’ 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.

 

Cytochrome P450 and family


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

 

 


QT interval


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


CYP3A substrates


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


P-glycoprotein (PgP)


Table 4: Drugs and P-glycoprotein (PgP)

Substrates

Inhibitors

Inducers

Colchicine

Verapamil

Carbamazepine

Digoxin

Amiodarone

Rifampicin

Morphine

Clarithromycin

St John’s Wort

Indinavir

Erythromycin

 

 

Ketoconazole

 

 

Quinidine

 


Drugs interacting with CYP3A substrates, inhibitors, inducers and PgP


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

Gastric pH


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

Anticoagulants


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

Other interactions


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

Method of administration


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

 

Conclusion


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.

Acknowledgements


I thank all those who have always challenged me; I appreciate their effort to make me brave enough to stand up for myself

Source(s) of Funding


N/A

Competing Interests


None

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