Tyrosine Kinase Inhibitors

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

Exam Important

  • All tyrosine kinase inhibitors are metabolized by CYP 3A4 enzymes, hence increased potential for drug interactions.
  • All tyrosine kinase inhibitors can be administered orally.
  • Imitinab is DOC for CML & gastro-intestinal stromal tumor (GIST).
  • Gefitinib & Erlotinib are tyrosine kinase inhibitors associated with epidermal growth factor receptor (EGFR).
  • Erlotinib is metabolized by CYP3A4 enzyme system.
  • Food increases 100% Erlotinib absorption.
  • Acneiform skin rash, diarrhea, anorexia and fatigue are most common adverse effects of Erlotinib.
  • Sorafenib Sunitinib are small molecules inhibiting multiple tyrosine kinases.
  • Pazopanib is approved for treatment of advanced renal cell carcinoma.

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

 
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