TYROSINE KINASE INHIBITORS

TYROSINE KINASE INHIBITORS

• All tyrosine kinase inhibitors are metabolized by CYP 3A4 enzymes.
  • Hence, increased potential for drug interactions.
• All tyrosine kinase inhibitors can be administered orally.

List of TK inhibitor drugs:

Drug	Target receptor for TK inhibition	Indications
Afatinib	EGFR, HER-2, HER-4	Non-small cell lung carcinoma (NSCLC)
Axitinib	VEGFR-1,2,3	Advanced renal cell carcinoma
Bosutinib	abl-bcr, src	CML
Ceritinib	ALK	NSCLC
Crizotinib	c-MET, ALK	Non-small cell lung carcinoma
Cabozantinib	c-MET, VEGFR-2	Medullary carcinoma thyroid
Dabrafenib	BRAF	Metastatic melanoma
Dasatinib	abl-bcr	CML
Erlotinib	EGFR	Non-small cell lung carcinoma  Pancreatic carcinoma
Gefitinib	EGFR	Non-small cell lung carcinoma
Ibrutinib	Btk	CLL
Imatinib	abl-bcr, c-KIT, PDGF	CML, GIST
Lapatinib	her-2/neu, erb-B2	Breast carcinoma
Lenvatinib	VEGF	I131 Refractory differentiated thyroid cancer
Nilotinib	abl-bcr	CML
Pazopanib	VEGFR-1,2,3 PDGFR α, β c-KIT	Advanced renal cell carcinoma
Ponatinib	abl-bcr	CML & Philadelphia positive ALL
Regorafenib	VDGFR2, TIE2	Colorectal carcinoma & GIST
Ruxolitinib	JAK 1,2	Myelofibrosis
Sorafenib	VEGFR, PDGFR RAF	Renal cell carcinoma & Hepatocellular carcinoma
Sunitinib	VEGFR, PDGFR c-KIT, FLT-3, RET	Renal cell carcinoma Pancreatic neuroendocrine tumors & GIST
Tofacitinib	JAK	Rheumatoid arthritis
Trametinib	MEK	Metastatic melanoma
Vandetanib	VEGFR, EGFR	Medullary carcinoma thyroid
Vemurafenib	BRAF	Malignant melanoma

Drugs included:

• Imatinib, Dasatinib, Nilotinib, Gefitinib, Erlotinib, Sorafenib, Sunitinib, Lapatinib, Pazopanib,

Important individual drug details:

1. Imitinab:

• Oral drug indicated for chronic phase of CML.
• MOA:
  • Acts by inhibiting tyrosine kinase activated due to abl-bcr fusion (t 9, 22; Philadelphia chromosome).
  • Competitive inhibitor of ATP-binding of abl kinase in the inactive conformation.
• Uses:
  • DOC for CML & gastro-intestinal stromal tumor (GIST).

2. Dasatinib & Nilotinib:

• Used in imatinib resistance case.

3. Gefitinib & Erlotinib:

• Tyrosine kinase inhibitors associated with epidermal growth factor receptor (EGFR).
• Uses:
  • Non-small cell lung cancer.

4. Erlotinib:

• • In EGFR mutations cases (Kras mutations cases are irresponsive).
• Metabolism:
  • Metabolized by CYP3A4 enzyme system.
  • Food increases 100% Erlotinib absorption.
• Uses: 
  • Especially effective in cases affecting women, nonsmokers, & persons of asian ethnicity, adenocarcinoma & bronchioalveolar carcinoma cases.
  • Also indicated for pancreatic carcinoma with gemcitabine.
• Adverse effects:
  • Most common – Acneiform skin rash, diarrhea, anorexia and fatigue.

5. Sorafenib & Sunitinib:

• Small molecules inhibiting multiple tyrosine kinases.
• Uses:
  • Both used in renal cell cancer.
  • Sorafenib – Indicated for hepatocellular cancer.

• • Sunitinib – GIST.
• Adverse effect: Hypertension.

6. Lapatinib:

• Inhibits tyrosine kinase associated with EGFR & her-2/neu receptors.
• Indicated for breast carcinoma.

7. Pazopanib:

• Multi-targeted tyrosine kinase inhibitor against VEGF receptors, PDGF receptor and c-kit.
• Uses: Approved for treatment of advanced renal cell carcinoma

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