Transcript CYP3A4 Inhibitors

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 kinases
can lead to uncontrolled growth and malignant
transformation.
• Many defective of tyrosine kinases and associated
proteins are oncogenic:
• V-src
• ABL
• EGFR-related family
Development
control
Roles of Tyrosine
In cancer
cells
Kinases
Differentiation
control
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
Ligand
Binding induces
dimerization
activation
of the intracellular
TK ( Protien kinase
cascade)
TK inhibitor
TK inhibitor
Strategies
for Targeting
Cancer Therapy
DYSREGULATION
OF TKTK
INin
CANCER
CELLS
• Fusion of
• Receptor
or
Dominant
• Non
Negative
protein
receptor
Imatinib
• With
Nilotinib
• Partener
• Protein
Gefitinib
Mutation
of
receptor
Erlotinib
TK
Imatinib
causing
Sorafenib
Constitutive
Activation
Neutralizing
Over
Antibody
expression
as
of
MAb
Or TK
receptor
Gefinitib
or ligend
Decrease in
factor
that
limit the
activity
as
Impaired
tyrosine
phosphatase
Tyrosine kinase targets for anticancer
agent
Small molecule inhibitor
Non
Temsirolimus
-Receptor
TK
TK
Multiple action
EGFRs
Receptor
PDGF
Tk
Monoclonal
antibodies
TK
Antibody
to
recepto TK
(EGFRs )
Antibody
to
ligand:
Anti
VEGF
angiogensis
TK
Dual Action Dual Action
Leflun
imatinib
Dual Action
Gefitinib
Erlotinib
Pazopanib
sunitinib
ZD6474
Imatinib
lapatinib
-omide
Sorafenib
Vatalanib
DualAction
ActionDasatinib
Nilotinib
Dual
cetuximab
trastuzumab
bevacizumab
EGFR Inhibitor
Erlotinib (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
NSCLC 250 mg / •
daily orally
Now it restricted to •
patient who already
received &benefited
from therapy.
1 week rest , subsequence cycle 1 mg /m2 for 3
week then 1 week rest.
Erlotinib 100 mg /day
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
the
Interstitial 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
Bioavilability
60%
60%
Execration
Hepatic 83%
Hepatic mainly
Plasma pk
Cmax2-4 hrs after dosing
Cmax3-7hrs after
dosing
hepatic
dysfunction
Dose adjustment only in very advanced liver
disease
As Erlotinib
Prengancy
Category D
Same
Pediatric
No study due to risk of dehydration
Same
Geriatric use
No differences in safety or pk than adult
Same
Imatinib mesylate (Gleevec®)
Approved by FDA in 2001
Tablets for oral use
INDICATIONS
Newly Diagnosed Philadelphia Positive
Chronic Myeloid Leukemia (Ph+ CML)
DOSAGE
400 mg/day
Ph+ CML in Blast Crisis (BC), Accelerated
Phase (AP) or Chronic Phase (CP) After
Interferon-alpha (IFN) Therapy
600 mg/day for adult patients in
accelerated phase or blast crisis.
Pediatric patients with Ph +CMLin chronic
phase
For newly diagnosed 340 mg/m/day
Ph+ Acute Lymphoblastic Leukemia
(ALL)
Kit+ Gastrointestinal Stromal Tumors
(GIST).
not exceeding 600 mg /day
After resistance to interferone therapy
260mg/m/day
600 mg/day for adult patients with
relapsed/refractory Ph+ ALL.
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,
•In normal cells
activation of the receptor
only occurs after binding
of the corresponding
ligand ( the stem cell
factor in the case of cKIT )
• Mutations in c-KIT result in a
constitutively active receptor
without the normally required
ligand binding.
• This constitutive
activation results in
stimulation of
numerous
downstream signal
transduction
pathways results in
malignancy.
Mechanism of Action .(CML)
• 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 cKIT.
.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
• Hepatotoxicity
occasionally severe
Liver 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 ANC
CML
<1.0x10^9/L
(starting dose
and/or
400mg)
Platelets
<50 x 10^9/L
or GIST
(starting dose either
400 mg or 600 mg)
ANC:absolute neutrophile count
1. Stop Gleevec until ANC
≥1.5 x 109/L and
platelets ≥75 x 10^9/L
or GIST (starting dose either 400
mg or 600 mg)
2. Resume treatment with
Gleevec at the original
starting dose of 400
mg or 600 mg
3. If recurrence of ANC
<1.0 x 10^9/L and/or
platelets <50 x 10^9/L, repeat step
1 and resume Gleevec at a
reduced dose (300
mg if starting dose was
400 mg, 400 mg if
starting dose was 600(
Accelerated
Phase CML
and Blast
Crisis
(starting dose 600mg)
ANC
<0.5 x 10^9/L
and/or
Platelets
<10 x 10^9/L
1. Reduce dose of Gleevec to 400
mg
3. If cytopenia persists 2
weeks, reduce further
to 300 mg
4. If cytopenia persists 4
weeks stop Gleevec until ANC
≥1 x 10^9/L and platelets
≥20 x 10^9/L and then
resume treatment at
300 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:
inhibitors
of the CYP3A4 activity
(e.g., ketoconazole, itraconazole,
erythromycin, clarithromycin).
Drugs that may
decrease
imatinib plasma
concentrations:
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 blockers
statins
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 Oglucuronidation 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 in
the accelerated Or blast crisis phases of the disease.
 Resulting in : relapse or no progression (persistence).
Imatinib resistance divided into the broad categories of primary
and secondary resistance:
1- Primary resistance to imatinib,
defined as an inability to achieve landmark response, is
comprised of the 2% of patients who fail to achieve hematologic
response and 8-13% who fail to achieve major or
complete cytogenetic response using early chronic phase
CML treated with imatinib at diagnosis as a benchmark.
2- Patients with secondary resistance—those
who achieve but subsequently lose relevant response—is
most straightforward for overt relapse such as loss of cytogenetic
or hematologic response and progression from
chronic 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.
Nilotinib
• 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).
Dasatinib
• It binds to multiple
conformations
of 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.
Brand name
Nilotinib
Tasigna®
Dasatinib
SPRYCEL®
Route of
administration
Oral, cap.
Oral,tab
Indications
• Philadelphia chromosomepositive 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 chromosomepositive acute lymphoblastic
leukemia (Ph+ ALL) with
resistance or intolerance to
prior therapy.
PKs
Nilotinib
Dasatinib
•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.
Nilotinib
Dose
Drug- drug
interactions
Dasatinib
400 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.
Clarithromycin,
moxifloxacin,
telithromycin,
Phenytoin, ketoconazole,
itraconazole, voriconazole,
cloazapine, ritonavir,
midazolam, digoxin
Rifampicin, phenytoin,
clozapine, digoxin, simvastatin,
famotidine.
Nilotinib
Dasatinib
ADVERSE
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….
Contraindications Do not use in patients with
hypokalemia,
hypomagnesemia, or long
QT syndrome, & breast
feeding.
Pregnancy
Breast feeding.
Category D
Nilotinib
Warning
Black Box Warning
Tasigna 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.
Dasatinib
• 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.
•Warning
•Nilotinib
•Dasatinib
•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.
SORAFENIB
Nexavar®
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
Due to
disruption of
normal
vasculature
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, anorexia
8. Teratogenicity and embryofetal toxicity
Drug Interactions
1- Docetaxel & Doxorubicin:
Increase in the AUC and Cmax when coadministered 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 (ChildPugh 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 (ChildPugh 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
Distribution
Metabolism
Elimination
Incomplete and variable
Systemic exposure increase with food
•99% bind to plasma protein
•Peak plasma levels are achieved 4 hrs after
ingestion.
•Steady-state concentration are reached in 6
– 7 days
Metabolized by the liver by the CYP3A4
and CYP3A5
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
21 days
Cycle
capecitabine 2,000 mg/m2/day on Days 1-14
should be taken with food or within 30 minutes after food
Drug Interactions
Drugs that stimulate CYP3A4
. Carbamazebine – rifamibicin,
Phenobarbital and St.John's wort
Inactivation of
Lapatinib
Drugs that inihibit CYP3A4
Ketoconazole, erythromycin
and clarithromycin
Lapatinib inhibits
human P-glycoprotein
Toxicity
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 angiogenesis
3- 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
Distribution
Metabolism
Elimination
•oral bioavailability 100%
•Not affected with food.
•90 – 95 % binds to plasma protein.
•Peak plasma level are achei ed 6 – 12 hrs.
•Steady state concentration reached 10 – 14
days.
Metabolized mainly by the liver by CYP3A4
produce primary active
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
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
Side Effects:
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.
Trastuzumab (Herceptin®)
Cetuximab (Erbitux®)
Bevacizumab (Avastin®)
Trastuzumab (Herceptin®)
•
•
•
•
•
Mechanism of Action
Mechanism of Resistance
Indications and Dosage Ranges
Drug Interactions
Special considerations
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 (Insulinlike growth factor-I receptor) which plays an
important role in tumor cell growth and survival
Indications and Dosage Ranges
Indication
Dosage 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.
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.
•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.
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 Considerations
1.
2.
3.
4.
5.
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.
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.
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.
Increased risk of myelosuppression when it is administered with
Chemotherapy
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.
Bevacizumab (Avastin®)
• Mechanism of Action
• Indications and Dosage Ranges
• Special considerations
Mechanism of Action
A tumor creates a network
of blood vessels
a 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 needs
2.Avastin may interfere with the growth of new blood vessels,
potentially helping to block further growth and spread of the cancer
3.Avastin may also cause the existing blood vessels to change in
ways that help the chemotherapy reach the tumor more effectively
Indications and Dosage Ranges
Indication
Dosage Range
Metastatic colorectal cancer
5mg/kg IV in combination with IV 5-FU
based-chemotherapy on an every 2-week
schedule
FDA approved use in combination with any
IV 5-FU based-chemotherapy in first line
therapy
Metastatic colorectal cancer
FDA approved use in combination with
FOLFOX4 (Oxaliplatin, Leucovorin, and
Fluorouracil) in second line therapy
Non-small cell lung cancer
10 mg/kg IV in combination with FOLFOX4
on an every 2 week schedule
15 mg/kg IV every three weeks
FDA approved in combination with
carboplatin/paclitaxel
Renal cell cancer
Remains investigational
Breast cancer
Remains 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 Considerations
1. 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 symptoms
Diphenhydramine 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