Presented by :

PharmD Group 5

Supervised by :

Dr. Nashaat Lotfy

• What is Tyrosine Kinase

• Non-receptor Tyrosine Kinase inhibitors

• Receptor Tyrosine Kinase inhibitors

• Monoclonal Antibodies

• Targeting antitumor therapy has been directed against cancer specific molecules & signling pathway , thus has more limited non specific toxicities.

• Tyrosine kinase = phosphorlation of tyrosine residue, this convert tyrosine kinase into active form (i.e switch on ).

• Tyrosine kinase play an important role in modulation of growth factor signling.

TK signaling pathway maintain normal cellular communication & maintain homeostasis (by prevent deregulated pathway or contributed to sensitivity towered apoptotic stimuli ). Excessive activation of receptor tyrosine kinasescan lead to uncontrolled growth and malignanttransformation.• Many defective of tyrosine kinases and associated

proteins are oncogenic:• V-src• ABL• EGFR-related family

Roles of Tyrosine Kinases

Differentiationcontrol

Cell cycle

control

Apoptosis

Immune

Response

scontrol

Developmentcontrol

Growth controlCell-cell

recognition

In cancer cells

Angiogensis

TYROSINE KINASE TARGETING

• 1-Receptor TK: • a-Platelet derived growth factor ( PDGFR)• b-Epidermal growth factor receptor (EGFR)

which include ( ErBB2,ErBB3,ErBB4 ,HER FAMILY).

• C-Vascular endothelial growth factor receptor (VEGF).

• D-stem cell factor receptor or (KIT receptor)

• 2- Non receptor TK : BCR ABL

LigandBinding induces

dimerization

activation of the intracellular

TK ( Protien kinase cascade(

TK inhibitor

TK inhibitor

DYSREGULATION OF TK IN CANCER CELLS Strategies for Targeting TK in Cancer Therapy

• Fusion of • Receptor

or• Non

receptor• With• Partener• Protein

Dominant Negative

protein ImatinibNilotinib

Over expression

of receptor TK or ligend

Neutralizing Antibody

as MAb

Or Gefinitib

Decrease in factor

that limit the

activity as

Impaired tyrosine

phosphatase

Mutation of receptor

TK causing

Constitutive Activation

GefitinibErlotinibImatinib

Sorafenib

Tyrosine kinase targets for anticancer agent

Small molecule inhibitorMonoclonal antibodies

Receptor TK

Non-Receptor

TKAntibody

to ligand:

Antibody to

recepto TK)EGFRs(

bevacizumabcetuximab

EGFRsTK

PDGFTk

VEGFTK

trastuzumab

imatinibErlotinibGefitinibDual Action

Imatinib

Antiangiogensis

sunitinibZD6474PazopanibDual Action

lapatinibLeflun

-omideDual ActionSorafenib

Dual ActionVatalanib

Dual Action DasatinibDual Action Nilotinib

Temsirolimus Multiple action

EGFR InhibitorErlotinib (traceva®) Gefitinib (IRESSA®)

ERLOTINIB (TRACEVA®) GEFITINIB IRESSA ®

Drug description

Oral tablet (25mg,100mg ,150mg ) 250 mg Oral tablet

Indication•1 -Non small cell lung cancer (NSCLC) 100mg \day after failure of one previous therapy

•2 -in pancreatic cancer : in combination with gemcitabine as first line therapy.

Gemcitabine: 1 mg /m2 weekly for 7 week then

1 week rest , subsequence cycle 1 mg /m2 for 3 week then 1 week rest.

Erlotinib 100 mg /day

•NSCLC 250 mg / daily orally

•Now it restricted to patient who already received &benefited from therapy.

Adverse effect

•Rash , diarrhoea , interstitial lung disease which can be fatal (0.8 % alone & 2.3 % in combination with gemcitabine ) , treatment should be inerrupted if cough , dyspnoea , fever.

• Myocardial infaraction( MI ) only in combination with gemcitabine (2.3%)

Same as Erlotinib but theInterstitial lung disease (1% ).

No MI

Drug interactions

1-CYP3A4 inhibitors as ketoconazole can increase concentration ( i..e toxicity).

2-CYP3A4 inducer : as Rifampicin can reduced it concentration (i.e efficacy).

3-P-glucoprotien inhibitor : as Ciclosporine : altered distribution or elimination of Erlotinib

4 -Antiacid , proton pump inhibitor , H2 antagonist → impaired absorption

5 -Smoking :reduce Erlotinib exposure .

As Erlotinib but no effect of smoking

Bioavilability60%60%

ExecrationHepatic 83%Hepatic mainly

Plasma pkCmax2-4 hrs after dosingCmax3-7hrs after dosing

hepatic dysfunction

Dose adjustment only in very advanced liver disease

As Erlotinib

Prengancy Category DSame

PediatricNo study due to risk of dehydrationSame

Geriatric useNo differences in safety or pk than adultSame

Imatinib mesylate (Gleevec®)

Approved by FDA in 2001

Tablets for oral use

INDICATIONSDOSAGE

Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML)

Ph+ CML in Blast Crisis (BC), Accelerated Phase (AP) or Chronic Phase (CP) After

Interferon-alpha (IFN) Therapy

Pediatric patients with Ph +CMLin chronic phase

400 mg/day

600 mg/day for adult patients in accelerated phase or blast crisis.

For newly diagnosed 340 mg/m/day not exceeding 600 mg /day

After resistance to interferone therapy 260mg/m/day

Ph+ Acute Lymphoblastic Leukemia (ALL)

600 mg/day for adult patients with relapsed/refractory Ph+ ALL.

Kit+ Gastrointestinal Stromal Tumors (GIST).

400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST.

A dose increase up to 800 mg daily (given as 400 mg twice daily) may be considered, as clinically indicated,

• Mutations in c-KIT result in a constitutively active receptor without the normally required ligand binding.

•In normal cells activation of the receptor only occurs after binding of the corresponding ligand ( the stem cell factor in the case of c-KIT )

• This constitutive activation results in stimulation of numerous downstream signal transduction pathways results in malignancy.

)CML( .Mechanism of Action

• Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the bcr-abl tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in chronic myeloid leukemia (CML).

• It inhibits proliferation and induces apoptosis in bcr-abl positive cell lines from Philadelphia chromosome positive chronic myeloid leukemia.

Mechanism of Action .)GISTs)

• Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and c-kit

• Not all GISTs express c-KIT mutations.• Activating mutations in the PDGFRA gene are

frequently demonstrated to occur( 3-5% of all GISTs) A mutated PDGFRA , which induces activation of the same signal transduction pathways as gain-of-function mutations in c-KIT.

.Mechanism of Action .

• Panel A shows the BCR-ABL oncoprotein with a molecule of adenosine triphosphate (ATP) in the kinase pocket.

• The substrate is activated by the phosphorylation of one of its tyrosine residues.

• It can then activate other downstream effector molecules.

• When imatinib occupies the kinase pocket (Panel B), the action of BCR-ABL is inhibited, preventing phosphorylation of its substrate.

ADVERSE REACTIONS

• Hepatotoxicityoccasionally severeLiver function (transaminases, bilirubin, and

alkaline phosphatase) should be monitored before initiation of treatment and monthly, or as clinically indicated.

If elevations in bilirubin >3 x institutional upper limit of normal (IULN) or in liver transaminases >5 x IULN occur

Gleevec should be withheld until bilirubin levels have returned to a <1.5 x IULN and

transaminase levels to <2.5 x IULN.

ADVERSE REACTIONS

• Hematologic Toxicity

Anemia , neutropenia , and thrombocytopenia.

Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as

clinically indicated

Dose Adjustments for Neutropenia and Thrombocytopenia

Chronic Phase CML (starting dose 400mg)

or GIST(starting dose either 400 mg or 600 mg)

ANC <1.0x10^9/Land/orPlatelets <50 x 10^9/L

1. Stop Gleevec until ANC≥1.5 x 109/L andplatelets ≥75 x 10^9/Lor GIST (starting dose either 400 mg or 600 mg)

2. Resume treatment withGleevec at the originalstarting dose of 400mg or 600 mg

3. If recurrence of ANC<1.0 x 10^9/L and/orplatelets <50 x 10^9/L, repeat step 1 and resume Gleevec at areduced dose (300mg if starting dose was400 mg, 400 mg ifstarting dose was 600(

ANC:absolute neutrophile count

Accelerated Phase CML and Blast Crisis(starting dose 600mg)

ANC <0.5 x 10^9/Land/orPlatelets <10 x 10^9/L

1. Reduce dose of Gleevec to 400mg

3. If cytopenia persists 2weeks, reduce furtherto 300 mg

4. If cytopenia persists 4weeks stop Gleevec until ANC≥1 x 10^9/L and platelets≥20 x 10^9/L and thenresume treatment at300 mg

ADVERSE REACTIONS

• Gastrointestinal Disorders

Gleevec is associated with GIT irritation ( nausea particularly if taken on empty stomach).

Gleevec should be taken with food and a large glass of water to minimize this problem.

•Fluid Retention and Edema

The probability of edema was increased with higher Gleevec dose and age >65 yearsand in 2%-6% of other adult CML patients taking Gleevec. In addition, other severe fluid retention: (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites

ADVERSE REACTIONS

• Dermatologic Toxicities

• Hemorrhage

• Arthralgia , myalgia ,and bone pain.

• Teratogenic

Metabolism and Elimination

• CYP3A4 is the major enzyme responsible for metabolism of imatinib.

• Other cytochrome P450 play a minor role in its metabolism.

• Elimination is predominately in the feces, mostly as metabolites (68% of dose) and urine (13% of dose).

Drug Interactions

• Drugs that May Alter Imatinib Plasma Concentrations

Drugs that may increase

imatinib plasma concentrations:

Drugs that may decrease

imatinib plasma concentrations:

inhibitors of the CYP3A4 activity

)e.g., ketoconazole, itraconazole, erythromycin, clarithromycin.(

inducers of CYP3A4 activity)e.g., dexamethasone,

phenytoin, carbamazepine, rifampin phenobarbital

Drug Interactions

• Drugs that May Have their Plasma Concentration Altered by Gleevec

CYP3A4 substrates

cyclosporine benzodiazepines,Dihydropyridine

calcium channel blockersstatins

Drug Interactions

• Because warfarin is metabolized by CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin.

• Gleevec inhibits acetaminophen O-glucuronidation at therapeutic levels. Systemic exposure to acetaminophen is expected to be increased when coadministered with Gleevec.

Resistance to imatinib is still a problem ,mainly in patients inthe accelerated Or blast crisis phases of the disease. Resulting in : relapse or no progression (persistence).

Imatinib resistance divided into the broad categories of primaryand secondary resistance:1- Primary resistance to imatinib,defined as an inability to achieve landmark response, iscomprised of the 2% of patients who fail to achieve hematologicresponse and 8-13% who fail to achieve major orcomplete cytogenetic response using early chronic phaseCML treated with imatinib at diagnosis as a benchmark.2- Patients with secondary resistance—thosewho achieve but subsequently lose relevant response—ismost straightforward for overt relapse such as loss of cytogeneticor hematologic response and progression fromchronic to advanced-stage disease.

Mechanisms of Imatinib resistance:

1. Over-expression of BCR/ABL & BCR/ABL point mutations in imtinib resistant leukemia: the relapse is characterized by reactivation of BCR/ABL kinase activity.

2. c-Kit & PDGFRa point mutations in GIST: an “enzymatic site” activating mutation which affects that catalytic portion of the KIT receptor kinase is associated with resistant to imatinib.

Mechanism of Imatinib resistance:

3. P-glycoprotein up regulation: i.e. over expression of multidrug resistance P-gp (efflux pump).

4. Alpha acid glycoprotein binding of imatinib: the plasma protein alpha 1 acid glycoprotein (AGP) has been proposed to bind to imatinib & prevent imatinib from reaching its target.

Strategies to overcome imatinib resistance:1- Combination therapy with imatinib: to improve response includes; the standard chemotherapeutic agents : cytosine arabinoside, daunorubicin, interferon alpha.2- Modulation of imatinib dosing: by administration of higher (than conventional) doses of imatinib.3- Second line therapy: Nilotinib, Dasatinib.

• It is a selective BCR/ABL tyrosine kinase inhibitor,• also it inhibits the receptor tyrosine kinases platelet-derived growth

factor receptor (PDGF-R) and c-kit, a receptor tyrosine kinase mutated and constitutively activated in most gastrointestinal stromal tumors (GISTs).

Nilotinib

Dasatinib

• It binds to multiple conformationsof the ABL kinase,• dasatinib inhibits BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFR-B. By targeting these kinases, dasatinib inhibits the overproduction of leukemia cells in the bone marrow of patients with CML and Ph+ALL and allows normal red cell, white cell, and blood platelet production to resume.

NilotinibDasatinibBrand nameTasigna®SPRYCEL®

Route of administration

Oral, cap.Oral,tab

Indications• Philadelphia chromosome-positive chronic myelogenous leukemia in adult patients resistant or intolerant to prior therapy.

• Ph+ acute lymphoblastic leukemia.

• Systemic mastocytosis

• Hypereosinophilic syndrome.

• treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase

chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy

including imatinib.

• treatment of adults with Philadelphia chromosome-positive acute lymphoblastic

leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.

NilotinibDasatinib

PKs•A – AUC ↑ 82% when given after high fat meals.

• D – 98% protein bound.

• M – hepatic: oxidation and hydroxylation.

• E – 90% eliminated in feces; t1/2 = 17 hrs.

• 94% protein bound.

• eliminated primarily by hepatic metabolism and excreted in feces.

• excreted <1% in the urine.

• primarily metabolized by CYP3A4;

• mean half life ≈ 4 to 6 h.

• not altered in absorption with co-administration of food.

NilotinibDasatinibDose400 mg orally twice

daily,approximately 12 hours apart and should not be taken with food.

70 mg orally twice a day, •Chronic phase CML: 100 mg once daily.

• Accelerated phase CML, myeloid or lymphoid blast phase CML, or Ph+ ALL: 70 mg

twice daily.

Administered orally, with or without a meal. Tablets should not be crushed or cut.

Drug- drug interactions

Clarithromycin, moxifloxacin, telithromycin,

Phenytoin, ketoconazole, itraconazole, voriconazole, cloazapine, ritonavir, midazolam, digoxin

Rifampicin, phenytoin, clozapine, digoxin, simvastatin, famotidine.

NilotinibDasatinibADVERSE

REACTIONS• QT prolongation and Sudden Deaths.

• Myelosuppression.

• Elevated serum lipase.

• Hepatotoxicity.

• Electrolyte abnormalities.

• Myelosuppression.

• Bleeding related events.

• Fluid retention.

• QT prolongation.

Side effects Rash, Prorates , Nausea

Neutropenia, Thrombocytopenia

Diarrhea, anorexia, colitis….

ContraindicationsDo not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome, & breast feeding.

Breast feeding.

PregnancyCategory D

NilotinibDasatinib

WarningBlack Box WarningTasigna prolongs the QT interval. Sudden deaths have been reported in patients receiving nilotinib. Tasigna should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome, Hypokalemia or hypomagnesemia must be corrected prior to Tasigna administration and should be periodically monitored. Drugs known to prolong the QT interval and strong CYP3A4 inhibitors should be avoided.

• Myelosuppression: Severe thrombocytopenia, neutropenia, and anemia may occur and require dose interruption or reduction. Monitor complete blood counts regularly

• Bleeding Related Events (mostly associated with severe thrombocytopenia): CNS

hemorrhages, including fatalities, have occurred. Severe gastrointestinal

hemorrhage may require treatment interruptions and transfusions.

•Nilotinib•Dasatinib

•Warning•Patients should avoid food 2 hours before and 1 hour after taking dose. Use with caution in patients with hepatic impairment. ECGs should be obtained to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, as well as following any dose adjustments.

•Use SPRYCEL

•with caution in patients requiring medications that inhibit platelet function or

•anticoagulants.

• Fluid Retention.

• QT Prolongation.

• Use SPRYCEL with caution in patients with hepatic

•impairment.

SORAFENIBNexavar®

Indications• Approved by the FDA on December 20, 2005 for the treatment of patients with

advanced renal cell carcinoma.

tumor progress

• The FDA has granted marketing authorization to Nexavar (sorafenib) tablets for the treatment of patients with hepatocellular carcinoma (HCC), the most common form of liver cancer, on November 19, 2007.

Mode Of Action

• Sorafenib is a small molecular inhibitor of several protein kinases (dual specificity kinases).

• Protein kinases are overactive in many of the molecular pathways that cause cells to become cancerous. These pathways include Raf kinase, PDGF (platelet-derived growth factor), VEGF receptor 2 and 3 kinases and c Kit the receptor for Stem cell factor.

• Sorafenib is unique in targeting the Raf/Mek/Erk pathway.

Dosage And Administration

• The recommended daily dose of Sorafenib is 400 mg (2 x 200 mg tablets) taken twice daily without food.

• Tablets should be taken on empty stomach, (at least 1 hour before or 2 hours after a meal).

• Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

Side effects

1. Risk of myocardial ischemia and/or infarction.

2. Risk of hemorrhage.3. Risk of hypertension.4. Risk of dermatologic toxicity (hand-foot

skin reaction)5. Risk of gastrointestinal perforation.6. Wound healing complications.7. Fatigue, weight loss, anorexia8. Teratogenicity and embryofetal toxicity

Due to disruption of

normal vasculature

Drug Interactions

1- Docetaxel & Doxorubicin: Increase in the AUC and Cmax when co-

administered with Sorafenib. 2- Fluorouracil: Increase and decrease in the AUC. 3- CYP3A4 Inducers concomitant administration of Sorafenib and

CYP3A4 Inducers resulted in reduction of sorafenib AUC.

4- CYP3A4 Inhibitors and CYP Isoform Substrates

Sorafenib metabolism is unlikely to be altered by CYP3A4 inhibitors.

Hepatic Impairment

• Sorafenib is cleared primarily by the liver.• Comparison of data across studies suggests that in HCC

patients with mild (Child-Pugh A) or moderate (Child- Pugh B) hepatic impairment, 400 mg doses of sorafenib appear

to be associated with AUC values that were 23 to 65% lower than those of other subjects without hepatic

impairment. The AUC of sorafenib is similar between HCC patients with mild (Child-Pugh A) and moderate (Child-

Pugh B) hepatic impairment. The pharmacokinetics of sorafenib have not been studied in patients with severe

(Child-Pugh C) hepatic impairment

•

Temsirolimus (Torisel®)

Indication

• Renal cell carcinoma (RCC ) as single • agent therapy .

Dosage and Administration

25 mg IV infused over 30–60 minutes once per week until disease progression.

Side effects

• 1-fatigue,• 2- skin rash , stomatitis • 3-Hematologic abnormalities

Drug Interaction & Dose Modification

1- Concomitant Strong CYP3A4 Inhibitors should be avoided (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Grapefruit juice.

If patients must be co-administered a strong CYP3A4 inhibitor, TORISEL dose reduction to 12.5 mg/week should be considered.

2- Concomitant Strong CYP3A4 Inducers

should be avoided (e.g. dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin, phenobarbital).

If patients must be co-administered a strong CYP3A4 inducer, based on pharmacokinetic studies, a TORISEL dose increase from 25 mg/week up to 50 mg/week should be considered.

Trade Name : Tykerb

Classification : Signal translation inhibitors

Mechanism of Action:

Small Cell Molecular Inhibitor of tyrosine Kinase

EGFR HER2

• inhibition of critical mitogenic and antiapoptotic signals involved in proliferation, growth, invasion/metastasis, angiogenesis, and response to chemotherapy and/or radiation therapy.

Pharmacokinetics

Absorption Incomplete and variable Systemic exposure increase with food

Distribution•99% bind to plasma protein •Peak plasma levels are achieved 4 hrs after ingestion.•Steady-state concentration are reached in 6 – 7 days

Metabolism Metabolized by the liver by the CYP3A4 and CYP3A5

Elimination Mainly hepatically – 2 % renally

Indications

Advanced metastatic breast cancer in combination with capecitabine ( prodrug converted to 5-fluorouracil at tumor site) in patients have received prior therapy including an anthracycline, taxane and trastuzumab

Dosage Regimen

1250 mg PO Days 1-21 continuously

one hour before or one hour after a meal

capecitabine 2,000 mg/m2/day on Days 1-14

should be taken with food or within 30 minutes after food

21 daysCycle

Drug Interactions

Drugs that stimulate CYP3A4 .Carbamazebine – rifamibicin,

Phenobarbital and St.John's wort

Inactivation of Lapatinib

Drugs that inihibit CYP3A4Ketoconazole, erythromycin

and clarithromycin Toxicity

Lapatinib inhibits human P-glycoprotein

Increased conc. Of substrate drugs

Lapatinib may inhibit the metabolism of Warfarin

Special Consideration

1. Use caution in patient with hepatic impairment, and dose reduction should be considered.

2. Lapatinib may cause reduction of LVEF. Monitor cardiac function at baseline and periodically during therapy.

3. QTprolongation is observed. Monitor QT parameter at baseline

4. Lapatinib should be taken one hour before or after a meal, and the daily dose should not be divided. When capecitabine is co-administered, capecitabine should be taken with a galss of water 30 min. after meals.

5. Avoid grapefruit

6. Closely monitor patient for diarrhea. Aggressive management should be followed

7. Pregnancy category D.

Side Effects

1. Diarrhea

2. Reduction of LVEF and QT prolongation.

3. Myelosuppression with anemia more common than

thrombocytopenia or neutopenia.

4. Fatigue and anorexia

5. Mild to moderate elevation of serum transaminases and serum

bilirubin.

6. Hand-food syndrome and skin rash.

Mechanism of Action: Sunitinib is oral small molecule that inhibits multiple receptor tyrosine kinases (RTKs), some of which are implicated in: 1- Tumor growth, 2- Pathologic angiogenesis3- Metastatic progression of cancer.

Sunitinib was identified as an inhibitor of 1- Platelet-derived growth factor receptors, 2- Vascular endothelial growth factor receptors , 3- Stem cell factor receptor, 4- Colony stimulating factor receptor Type 1 (CSF-1R)

Indications

FDA approved Sunitinib in 2006 for the treatment of adults with:

1- Advanced renal cellular carcinoma

2- Gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate.(Gleevec®)

Recommended dose :

50 mg oral dose taken once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2).

SUTENT may be taken with or without food.

Pharmacokinetics

Absorption •oral bioavailability 100% •Not affected with food.

Distribution•90 – 95 % binds to plasma protein. •Peak plasma level are achei ed 6 – 12 hrs. •Steady state concentration reached 10 – 14 days.

Metabolism Metabolized mainly by the liver by CYP3A4 produce primary active

Elimination Mainly hepatically – 16 % renally

Special Considerations :

1. Baseline and periodic evaluation of LVEF should be performed.

2. Use with caution in patient with underlying cardiac disease,

especially those who presented with cardiac events within 12

months prior to initiation of Sunitinib such as MI & CHF.

3. In presence of clinical manifestations of CHF, discontinuation if

Sunitinib is recommended or reduction of the dose

4. Closely monitoring of blood pressure ( Hypertension)

5. Monitoring of adrenal insufficiency in patient who experience

increased stress such as surgery, trauma or sever infection.

6. Closely monitoring of thyroid function, as Sunitinib results is

hypothyroidism.

7. Avoid grapefruit or grapefruit juice.

8. Pregnancy category D. Breast feeding should be avoided

1. Hypertension.

2. Yellowish discoloration of

the skin, skin rash,

depigmentation of hair

and/or skin

3. Bleeding complication with

epistaxis.

4. Fatigue and asthma.

5. Diarrhea

6. Myelosuppression with

neutropenia.

7. Adrenal insufficiency and

hypothyroidism.

Side Effects: Drug Interactions

CYP3A4 Inducers ( ↓Sreum level of Sunitinb) Dexamethasone, phenytoin, carbamazepine, rifampin,Phenobarbital, St. John’s Wort

CYP3A4 Inhibitors ( ↑Sreum level of Sunitinb) Ketoconazole, itraconazole, clarithromycin , saquinavir , grapefruit

Trastuzumab (Herceptin®)

Bevacizumab (Avastin®)

Cetuximab (Erbitux®)

• Mechanism of Action

• Mechanism of Resistance

• Indications and Dosage Ranges

• Drug Interactions

• Special considerations

Trastuzumab (Herceptin®)

Mechanism of Action

•Breast cancer cells divide and grow when human epidermal growth factor protein attaches itself to another protein known as HER2 (human epidermal growth factor receptor-2), which is found on the surface of some breast cancer cells.

•Herceptin blocks this process by attaching itself to the HER2 protein i.e Inhibits HER-2 intercellular signalling pathways.

• Herceptin also works by attracting the body’s own immune cells to help destroy the cancer cells.

HER2 Testing (to inhibit the proliferation of human tumor cells that overexpress HER2)Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy because these are the only patients studied and for whom benefit has been shown.

Mechanism of Resistance

• Mutation in the HER-2/neu growth factor receptor leading to decreased binding affinity to trastuzumab.

• Decreased expression of HER-2/neu receptors.

• Activation/induction of alternative cellular signalling pathways, such as IGF-IR (Insulin-like growth factor-I receptor) which plays an important role in tumor cell growth and survival

Indications and Dosage Ranges

IndicationDosage Range

Metastatic breast cancer – First-line therapy in combination with paclitaxel

•Recommended loading dose of 4 mg/kg IV administered over 90 minutes, followed by maintenance dose of 2 mg/kg IV on a weekly basis.

•Alternative schedule is to give a loading dose of 9 mg/kg IV administered over 90 minutes, followed by maintenance dose of 6 mg/kg IV every 3 weeks.

Matastatic breast cancer – Second and third-line therapy as a single agent

FDA-approved for the adjuvant therapy of node-positive, HER2-overexpressing breat cancer as part of the treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel.

Drug Interactions

• Anthracyclines, taxanes – Increased risk of cardiotoxicity when trastuzumab is used in combination with anthracyclines and/or taxanes.

• Administration of paclitaxel in combination with Herceptin resulted in a 1.5-fold increase in trastuzumab serum levels

Special Considerations1. Caution should be exercised in treating patients with pre-existing

cardiac dysfunction. Careful baseline assessment of cardiac function before treatment and frequent monitoring of cardiac while on therapy. Trastuzumab should be stopped immediately in patients who develop clinically significant congestive heart failure.

2. Administer initial loading dose of 90 minutes and then observe patient for 1 hour following completion of the loading dose. Carefully monitor for infusion-related symptoms.

Diphenhydramine and acetaminophen are used for treatment.

3. Maintenance doses are administered over 30 minutes if loading dose was well tolerated without fever and chills.

However, if fever and chills were experienced with loading dose, need to administer over 90 minutes.

4. Increased risk of myelosuppression when it is administered with Chemotherapy

5. Pulmonary toxicity have been reported.

Cetuximab (Erbitux®)

Mechanism of Action• EGFR (epidermal growth factor receptor) is overexpressed in a broad

range of human solid tumors, including colorectal cancer, head and neck cancer, non-small cell lung cancer, pancreatic cancer, and breast cancer.

• Cetuximab is directed against the epidermal growth factor receptor (EGFR), which leads to inhibition of autophosphorylation and inhibition of EGFR signalling.

 

Indications• Colorectal cancer in combination with irinotecan or as monotherapy in

patients who are deemed to be irinotecan-intolerant- FDA approved• Head and neck cancer - FDA approved• Pancreatic cancer – remains investigational.• Non-small cell lung cancer – remains investigational.• Breast cancer – remains investigational.

• Mechanism of Action

• Indications and Dosage Ranges

• Special considerations

Bevacizumab (Avastin®)

Mechanism of Action

A tumor creates a network of blood vesselsa process called angiogenesis.

An anti-angiogenic agent may inhibit blood vessel formation, which starves the tumor.

Avastin is thought to work by blocking one of the key signals that causes angiogenesis. Avastin blocks a protein called vascular endothelial growth factor (VEGF).

This may allow Avastin to affect the tumor in different ways:1.Avastin may cause the blood vessels to shrink away from the tumor, blocking the supply of oxygen and nutrients that the tumor needs2.Avastin may interfere with the growth of new blood vessels, potentially helping to block further growth and spread of the cancer3.Avastin may also cause the existing blood vessels to change in ways that help the chemotherapy reach the tumor more effectively

Indications and Dosage RangesIndicationDosage Range

Metastatic colorectal cancerFDA approved use in combination with any IV 5-FU based-chemotherapy in first line therapy

5mg/kg IV in combination with IV 5-FU based-chemotherapy on an every 2-week schedule

Metastatic colorectal cancerFDA approved use in combination with FOLFOX4 (Oxaliplatin, Leucovorin, and Fluorouracil) in second line therapy

10 mg/kg IV in combination with FOLFOX4 on an every 2 week schedule

Non-small cell lung cancerFDA approved in combination with carboplatin/paclitaxel

15 mg/kg IV every three weeks

Renal cell cancerRemains investigational

Breast cancerRemains investigational

N.B: for advanced cell carcinoma, 7.5 mg/kg IV ever 3 weeks when used in combination with capecitabine-based regimens for advanced colorectal cancer.

Special Considerations1. Patients should be warned of the increased risk of arterial

thromboembolic events (MI or stroke).Risk factors are age > 65 years old, history of angina, stroke.

2. Patients should be warned of serious hemorrhage resulting from hemoptysis in patients with Non-small cell lung cancer.Patients with recent hemoptysis should not receive Bevacizumab.

3. GI perforations and wound dehisecence (bursting open of a surgically closed wound)Bevacizumab should be taken at least 28 days after any surgical and/or invasive procedures

4. Carefully monitor for infusion related symptomsDiphenhydramine and acetaminophen are used for treatment.

Special Considerations “Cont’d”5. Bevacizumab can result in grade 3 hypertension

Use with caution in patients with uncontrolled hypertension

increase the dose of antihypertensive and/ or addition of another antihypertensive medication

6. It can result in protein uria with nephrotic syndrome

It should be terminated in patients that develop the nephrotic syndrome

7. It can result in Reversible Posterior Leucoencephalopathy Syndrome (RPLS) manifested by neurologic disturbances,

it can occur from 16 hours to 1 year after initiation of therapy

MRI is necessary to confirm diagnosis