presented by : pharmd group 5 supervised by : dr. nashaat lotfy
TRANSCRIPT
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