oral TKI's

1. ORAL TYROSINE KINASE
INHIBITORS

2. 1. BCR-ABL Tyrosine Kinase Inhibitors(TKI)
Imatinib Mesylate,
Dasatinib,
Nilotinib,
Bosutinib
Ponatinib
2. Epidermal Growth Factor Receptor - TKI
Gefitinib,
Lapatinib,
Erlotinib
3. Vascular Endothelial Growth Factor – TKI
Vatalanib,
Sunitinib,
Sorafenib,
Pazopanib

3. IMATINIB(Gleevac)
• First molecularly targeted protein kinase inhibitor to
receive FDA approval
• MOA: Binds to a segment of the BCR- ABL tyrosine
kinase domain that fixes it in a closed or non-functional
state
• Indications:
- Chronic myelogenous leukemia( CML)
- Acute lymphoblastic leukemia (ALL)
- Gastrointestinal Stromal Tumors
- Myelodysplastic/Myeloproliferative Diseases
- Hypereosinophilic Syndrome/Chronic Eosinophilic
Leukemia
- Dermatofibrosarcoma Protuberans

4. IMATINIB
• Dosage :
- CML
1) Chronic phase , initial therapy
 400 mg OD P.O – increase upto 600 mg OD
2) Accelerated phase or blast crisis
 600 mg OD P.O – increase upto 800 mg OD
• Half life –18 hours

5. IMATINIB
• Toxicity
- GI – Nausea, vomiting, abdominal pain
- Edema
- Diarrhoea
- Muscle cramps
- Fatigue
- Skin rash
- Cytopenias

6. DASATINIB(Sprycel)
• MOA: Binds to both the open and closed
configuration of BCR- ABL kinase
• Indications
– Treatment of adults with chronic, accelerated, or
myeloid or lymphoid blast phase CML
– Treatment of adults with Philadelphia-chromosome
(+) ALL with resistance or intolerance to prior therapy
• Dosage : 100 mg OD (chronic phase)
70 mg OD (accelerated phase)
• Half life: 3-5 hrs

7. NILOTINIB(Tasigna)
• Indications: In adult patients with CML who are
resistant or intolerant to Imatinib
• Dosage : 400 mg BD ( both chronic and acc phase)
• Half life – 15 -17 hrs
• Toxicities :
- Thrombocytopenia and Neutropenia
- QT-prolongation
- Elevated liver enzymes
- Electrolyte abnormality (hyper & hypo K, hypo
Mg, Phos, Ca, Na)

8. GEFITINIB(Iressa, Geftib, Geftinat)
• MOA: Inhibit the EGFR tyrosine kinase by virtue of
competitive blockade of ATP binding
• Indications
Non-small Cell Lung Cancer (NSCLC)
Monotherapy for continued treatment of locally
advanced or metastatic NSCLC after failure of both
platinum-based and Docetaxel regimens
• Half life : 48 hrs
• Dosage : 250 mg OD

9. GEFITINIB
• Toxicities
 Dermatologic
– Rash, acne, xerosis, pruritus
 Gastrointestinal
– Diarrhea, Nausea, vomiting, anorexia
 Ocular
– Pain and corneal erosion/ulcer, aberrant eyelash
growth
Pulmonary
-- Interstitial lung disease, consisting of interstitial
pneumonia, pneumonitis, and alveolitis

10. ERLOTINIB(Tarceva)
• MOA: Inhibitor of HER1/EGFR tyrosine kinase.
• Indications :
– First-line treatment of patients with locally
advanced, unresectable, or metastatic pancreatic
cancer in combination with Gemcitabine.
– Second-line treatment of patients with locally
advanced or metastatic non–small cell lung cancer
Dosage: 150 mg OD
Half life: 41 hrs

11. ERLOTINIB
• Toxicities
 Pulmonary
- Dyspnea , cough
 Rash
 Gastrointestinal
– Diarrhea , anorexia , nausea/vomiting
 Fatigue
 Ocular
– Irritation, conjunctivitis and keratoconjunctivitis sicca , corneal
ulcerations
 Hepatotoxicity
– Asymptomatic  in liver enzymes, including hyperbilirubinemia
 Bleeding events
– Gastrointestinal bleeds, elevations in INR values in patients receiving
concomitant warfarin administration

12. LAPATINIB(Tykerb)
• MOA: 4-anilinoquinazoline kinase inhibitor of the
intracellular tyrosine kinase domains of both EGFR
and HER2 receptors
• INDICATION:
Metastatic Breast Cancer in combination with
Capecitabine in patients whose tumors overexpress
HER2 and who have received prior therapy including an
Anthracycline, a Taxane, and Trastuzumab

13. LAPATINIB
DOSAGE: 250 mg tablets
– In combination with Capecitabine, for the treatment of
advanced or metastatic breast cancer which overexpresses
HER2 and have received prior therapy including an
Anthracycline, a Taxane, and Trastuzumab.
– 1250mg (5 tabs) PO once daily, Days 1-21 on an empty
stomach
HALF LIFE : 24 hrs

14. • Toxicities
When combined with Capecitabine
• Diarrhea
• Palmar-plantar erythrodysesthesia
• Nausea/vomiting
• Rash
• Fatigue
• Decrease in LVEF
• ECG changes

15. SUNITINIB(Sutent)
MOA: VEGF –TKI
Indications :
- RCC
- GIST
- PNET
 Dosage: 12.5 mg, 25 mg, 50 mg capsules
- For advanced RCC and GIST
• 50 mg PO once daily, on a schedule of 4 weeks on
treatment followed by 2 weeks off
• Half life – 40 -60 hrs

16. SUNITINIB
Toxicities
• QT-prolongation
• Left Ventricular Dysfunction
• Hemorrhagic Events
• Hypertension (30%)
• Hypothyroidism – baseline thyroid function and monitor
for signs
• Adrenal Insufficiency
• GI distress
– Diarrhea, nausea, vomiting, stomatitis, dyspepsia
• Skin discoloration
• Fatigue

17. SORAFENIB(Nexavar)
• MOA: Inhibits the VEGFR and PGDFR
• Indications:
- RCC
- HCC
• Dosage: 400 mg BD
• Toxicities:
- Hand-foot syndrome, alopecia, rash
- Diarrhea or constipation
- Nausea/vomiting, abdominal pain
- High blood pressure
- Bleeding
- Neuropathy, joint pain
- Dyspnea
• Half life – 20-40 hrs

18. VATALANIB
• MOA: Inhibits all VEGFR but most selective for
VEGFR-2
• It is being studied as a single agent and in
combination with chemotherapy in patients with
1. Colorectal cancer and liver metastases,
2. Advanced prostate cancer
3. Renal cell cancer
4. Relapsed/refractory Glioblastoma multiforme

19. PAZOPANIB(Votrient)
• MOA: VEGFR and PDGFR inhibitor
• Dose : 800 mg OD
• Indications :
- RCC
- Soft tissue sarcoma
• Toxicites:
- Increased liver enzymes
- Malaise