This document discusses tyrosine kinase inhibitors, which are drugs that target tyrosine kinases. It begins by introducing tyrosine kinases and their role in cell signaling pathways. It then describes several important tyrosine kinase inhibitors, including BCR-ABL inhibitors like imatinib, dasatinib, and nilotinib; EGFR inhibitors like gefitinib and erlotinib; and VEGF inhibitors like sunitinib and sorafenib. For each drug, it provides information on mechanisms of action, pharmacokinetics, dosing, toxicity profiles, and FDA-approved indications. The document concludes by discussing mechanisms of resistance to BCR-ABL kinase inhibitors.

1. TYROSINE KINASE
INHIBITORS
PRESENTED BY:
Y.VIJAY
FINAL YEAR POST GRADUATE
DEPARTMENT OF PHARMACOLOGY
OSMANIA MEDICAL COLLEGE

2. CONTENTS
• INTRODUCTION
• TYPES OF TYROSINE KINASES
• ROLE OF KINASES IN SIGNALLING
PATHWAYS
• DRUGS TARGETTING TYROSINE
KINASES
• CONCLUSION
• REFERECES

3. INTRODUCTION
• PROTEIN KINASES:
• Protein kinases are a group of enzymes
that possess a catalytic subunit that
transfers the gamma (terminal)phosphate
from nucleotide triphosphates (often ATP)
to one or more amino acid residues in a
protein substrate side chain, resulting in a
conformational change affecting protein
function.

4. CATEGORIES OF PROTEIN KINASES
• Classified into three different categories:
1. Kinases that specifically phosphorylate
tyrosine residues
2. Kinases that phosphorylate serine and
threonine residues, and
3. Kinases with activity toward all three
residues.

5. TYPES OF TYROSINE KINASES
• Tyrosine kinases can be further
subdivided into
1. Receptor tyrosine kinases
eg: EGFR, PDGFR, FGFR
2. Non-receptor tyrosine kinases
eg: SRC, ABL, FAK and Janus kinase

6. T Y OSI N KI N
R E ASE ST R U T U E
C R
Extracellular
Domain
Transmembrane
Domain
TK Intracellular
Domain

7. RTK structure/function
Regulatory
domains

8. Oncogenic activation of Tyrosine kinase
• Normally the level of cellular tyrosine
kinase phosphorylation is tightly
controlled by the antagonizing effect of
tyrosine kinase and tyrosine
phosphatases.
• Some Common mechaninsms of
oncogenic activation:
1. Activation by mutation
2. BCR-ABL and human leukemia

9. TYROSINE KINASE INIBITORS
1. BCR-ABL Tyrosine Kinase Inhibitors eg: Imatinib
Mesylate, Dasatinib, and Nilotinib.
2. Epidermal Growth Factor Receptor
TyrosineKinase Inhibitors eg: Gefitinib, Lapatinib.
3. Vascular Endothelial Growth Factor
TyrosineKinase Inhibitors eg. Semaxinib, Vatalanib,
Sunitinib, Sorafenib.

10. BCR-ABL Tyrosine Kinase Inhibitors
• Mechanism of action :
• IMATINIB & NILOTINIB: bind to a
segment of the kinase domain that fixes
the enzyme in a closed or nonfunctional
state, in which the protein is unable to bind
its substrate/phosphate donor, ATP.
• DASATINIB: binds both the open and
closed configuration of BCR-ABL kinase.

11. BCR-ABL Tyrosine Kinase Inhibitors
• PHARMACOKINETICS 0f Imatinib / Dasatinib
• Absorption
– Oral bioavailability ~ 98%
• Distribution – highly protein bound
• Metabolism - Primarily by CYP3A4
• Elimination
– Fecal ~ 65-80% renal ~ 10-13%
– Half life = Imatinib-18 hrs, N-desmethyl derivative- 40 hrs
Dasatinib- 3-5 hrs
Nilotinib- 17 hrs

12. IMATINIB MESYLATE
• First molecularly targeted protein kinase
inhibitor to receive FDA approval.
• It targets the BCR-ABL tyrosine kinase,
which underlies chronic myelogenous
leukemia (CML).
• BCR-ABL tyrosine kinase is present in
virtually all patients with chronic
myelogenous leukemia (CML) and some
patients with acute lymphoblastic leukemia
(ALL)

13. IMATINIB MESYLATE
Dosing and Administration
• Treatment of Philadelphia chromosome(+) chronic
myelogenous leukemia
– Chronic phase, initial therapy
• 400 mg PO once daily - continue as long as the
patient continues to benefit
• May increase to 600 mg PO once daily
– Accelerated phase or blast crisis
• 600 mg PO once daily - continue as long as the
patient continues to benefit
• May increase to 800 mg/day PO

14. IMATINIB MESYLATE
• Toxicity
• Gastrointestinal
– Nausea, vomiting, abdominal pain
• Edema
– Periorbital edema or peripheral edema in the lower
extremities
• Diarrhea
• Muscle cramps
• Fatigue
• Skin rash
• Cytopenias

15. Imatinib (Gleevec®)
FDA Approved Indications
• Chronic Myeloid Leukemia
• Pediatric CML
• Acute Lymphoblastic Leukemia
• Gastrointestinal Stromal Tumors
• Myelodysplastic/Myeloproliferative
Diseases
• Aggressive Systemic Mastocytosis
• Hypereosinophilic Syndrome/Chronic
Eosinophilic Leukemia
• Dermatofibrosarcoma Protuberans

16. DASATINIB
• Multi-kinase inhibitor
• BCR-ABL, SRC family, c-KIT, EPHA2,
PDGFRβ
• FDA Approved 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

17. NILOTINIB
• Indication: treatment of chronic phase
and accelerated phase Philadelphia
chromosome positive chronic
myelogenous leukemia (CML) in adult
patients resistant to or intolerant to prior
therapy that included imatinib.

18. NILOTINIB
• Pharmacokinetics
• Absorption
– Peak plasma levels – 3 hours
– Approximately 30% of an oral dose of Nilotinib is
absorbed after administration
– Food (fatty meal) increases absorption
• Distribution
– Highly protein bound
– Plasma concentrations reach a steady state only after
8 days of daily dosing

19. NILOTINIB
Toxicities
• Thrombocytopenia and Neutropenia
• QT-prolongation – with sudden death
reported
• Liver function abnormality – elevated
bilirubin,AST/ALT and alkaline
phosphatase
• Electrolyte abnormality ( hyper and hypo
K, hypo Mg, Phos, Ca, Na)

20. Mechanism of resistance to Bcr-Abl
kinase inhibitors
• POINT MUTATIONS
CONTACT POINTS BETWEEN Imatinib and the
enzyme become the sites of mutation.
• Amplification of Wild type of Kinase gene
• Philadelphia –ve clones.

21. Epidermal Growth Factor Receptor
TyrosineKinase Inhibitors
• Gefitinib,
• Erlotinb
• Lapatinib

22. Epidermal Growth Factor Receptor
TyrosineKinase Inhibitors
• Mechanism of Action of Gefitinib / Erlotinib
Inhibit the EGFR tyrosine kinase by virtue of
competitive blockade of ATP binding
• Selectively inhibits EGFR-TK
Blockage of downstream EGFR signal transduction
pathways, cell cycle arrest, and inhibition of
angiogenesis

23. Epidermal Growth Factor Receptor
TyrosineKinase Inhibitors
• Pharmacokinetics of Gefitinib / Erlotinib
Absorption
– Peak plasma levels occurs 3-7 hours after dosing
– Mean bioavailability of 60%
– H2 Blockers and Proton pump inhibitors reduce plasma
concentrations.
Distribution
– 90% protein bound
Metabolism
– Predominantly via CYP3A4
Elimination
– Half life – Gefitinib- 48 hrs, Erlotinib- 36 hrs
– Fecal 86%, renal elimination < 4%

24. GEFITINIB
• Toxicities
• Dermatologic
– Rash, acne, xerosis, pruritus
• Gastrointestinal
– Diarrhea, Nausea, vomiting, anorexia
• Ocular
– Pain and corneal erosion/ulcer, aberrant
eyelash growth

25. GEFITINIB
Toxicities
• Pulmonary
– Interstitial lung disease, consisting of interstitial
pneumonia, pneumonitis, and alveolitis
– In the event of acute onset or worsening of
pulmonary symptoms (e.g., dyspnea, cough,
fever), gefitinib treatment should be interrupted
and the symptoms promptly investigated
– If interstitial lung disease is confirmed, gefitinib
therapy should be discontinued

26. GEFITINIB
• Drug Interactions
• CYP 3A4 inducers and inhibitors
• Warfarin: reports of elevations in INR
values and/or bleeding events
– Monitor INR regularly
• H2-blockers and proton pump inhibitors:
may ↓ plasma concentrations
– May potentially reduce Gefitinib efficacy

27. GEFITINIB
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
• PRESENT INDICATION: NSCLC – patient’s with
proven response prior to FDA “withdrawal” of
approval or on a clinical trial

28. ERLOTINIB
It is a Quinazolinamine inhibitor of HER1/EGFR
tyrosine kinase.
INDICATIONS
– approved for second-line treatment of patients with
locally advanced or metastatic non–small cell lung
cancer.
– Erlotinib also is approved for first-line treatment of
patients with locally advanced, unresectable, or
metastatic pancreatic cancer in combination with
Gemcitabine.
Unlabeled Uses
– Treatment of Squamous cell head and neck cancer

29. ERLOTINIB
Mechanism of Action:
• Blockage of downstream EGFR signal
transduction pathways, cell cycle arrest,
and inhibition of angiogenesis
• Erlotinib competitively inhibits ATP binding
at the active site of the kinase

30. ERLOTINIB
ADVERSE DRUG REACTIONS
• Pulmonary (not life-threatening)
– Dyspnea
– cough (33%)
• Rash (75%)
– Median time to onset 8 days (2-14 days)
• Gastrointestinal
– Diarrhea (54%, onset ≈12 days)
– anorexia ,
– nausea/vomiting (33%/23%)
• Fatigue (52%)

31. ERLOTINIB
ADVERSE DRUG REACTIONS
• Ocular
– Irritation, conjunctivitis (12%) and keratoconjunctivitis
sicca (12%), corneal ulcerations; reports of NCI CTC
grade 3 conjunctivitis and keratitis
• Hepatotoxicity
– Asymptomatic ↑ in liver enzymes, including
hyperbilirubinemia
• Bleeding events
– Gastrointestinal bleeds, elevations in INR values in
patients receiving concomitant warfarin administration

32. LAPATINIB
• LAPTINIB is a 4-anilinoquinazoline kinase
inhibitor of the intracellular tyrosine kinase
domains of both EGFR and HER2 receptors
• Mechanism of Action
Lapatinib and other pan-HER inhibitors block both
ErbB1 and ErbB2 and bind to an internal site on
the receptor (usually the ATP-binding pocket)
• It also binds to inhibits a truncated form of HER2
receptor that lacks a Trastuzumab binding domain.

33. LAPATINIB
• 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

34. LAPATINIB
• Pharmacokinetics
• Absorption
– Peak plasma levels – 4 hours
– Food increases absorption
• Distribution
– Highly protein bound
• Metabolism
– Extensive metabolism via CYP3A4, CYP3A5
• Elimination
– Half-life = 24 hours
– Hepatic metabolism

35. LAPATINIB
• Dosage and Administration
• Dosage Forms
– 250 mg tablets
• Administration
– 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

36. LAPATINIB
• Dosage adjustment
• Renal – No adjustments.
• Hepatic
– Severe impairment: dose reduction to
750mg/day should be considered
• Cardiac
– Therapy should be stopped for:
• > Grade 2 LVEF dysfunction
• LVEF less than lower limit of normal

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

38. Vascular Endothelial Growth
Factor TyrosineKinase Inhibitors
1. Semaxinib [with drawn]
2. Vatalanib,
3. Sunitinib,
4. Sorafenib.

39. SUNITINIB
• Mechanism of Action
• Inhibitor of multiple receptor tyrosine
kinases, some of which are implicated in
tumor growth, pathologic angiogenesis,
and metastatic progression of cancer.
• competitively inhibits the binding of ATP to
the tyrosine kinase domain on the VEGF
receptor-2

40. SUNITINIB
• Pharmacokinetics
• Absorption
– Peak plasma levels occur 6-12 hours after dosing
– Food has no effect on bioavailability
• Distribution
– 90 - 95% protein bound
• Metabolism
– Predominantly via CYP3A4

41. SUNITINIB
• Pharmacokinetics
• Sunitinib is metabolized by CYP3A4 to produce an
active metabolite SU12662
• the t1/2 of which is 80-110 hours
• steady-state levels of the metabolite are reached after
~2 weeks of repeated administration of the parent
drug.
• The pharmacokinetics of Sunitinib are not affected by
food intake.

42. SUNITINIB
• Pharmacokinetics
• Elimination
– Primarily via feces (61%)
– 16% renal elimination
– Half life: Parent compound (40-60hrs), active
metabolite (80-110hrs)

43. SUNITINIB
• Dosage and Administration
• Dosage Forms
– 12.5 mg, 25 mg, 50 mg capsules
• Administration
– Oral, with or without food
• Dosing
– For advanced RCC and GIST
• 50 mg PO once daily, on a schedule of 4 weeks on
treatment followed by 2 weeks off

44. SUNITINIB
Toxicities
• QT-prolongation
• Left Ventricular Dysfunction
• Hemorrhagic Events
• Hypertension (30%)
• Hypothyroidism – baseline thyroid function and
monitor for signs

45. SUNITINIB
Toxicities
• Adrenal Insufficiency
• GI distress
– Diarrhea, nausea, vomiting, stomatitis, dyspepsia
• Skin discoloration
• Fatigue

46. SORAFENIB
Mechanism of Action
• Multi-kinase inhibitor
• Targets RAF/MEK/ERK signaling pathway to inhibit
cell proliferation
• Inhibits the VEGFR-2/PDGFR-β signaling cascade to
inhibit angiogenesis

47. SORAFENIB
Pharmacokinetics
• Absorption
– Peak plasma levels achieved in ~3 hours
– Food reduced bioavailability by ~29%
• Distribution
– Protein binding 99.5%

48. SORAFENIB
Pharmacokinetics
• Metabolism
– Primarily by CYP3A4
– Eight metabolites identified
– Pyridine N-oxide has shown in vitro potency
similar to the parent drug.
• Excretion
– 77% Feces
– 19% Urine

49. SORAFENIB
Toxicities
• Hand-foot syndrome, alopecia, rash
• Diarrhea or constipation
• Nausea/vomiting, abdominal pain
• Fatigue
• High blood pressure
• Bleeding
• Neuropathy, joint pain
• Dyspnea

50. VATALANIB
• Small molecule protein kinase inhibitor that
inhibits angiogenesis
• It inhibits all known VEGF receptors, as well
as platelet-derived growth factor receptor-beta
and c-kit.
• Most selective for VEGFR-2.

51. VATALANIB
• 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.

52. SUMMARY
• Targeted therapy provides a new approach for
cancer therapy that has the potential for avoiding
some of the drawbacks associated with cytotoxic
chemotherapy
• At the present time, tyrosine kinase inhibitors serve
more as second- or third-line therapies rather than
as primary therapy.
• For the tyrosine kinase inhibitors to have a primary
role in therapy, there has to be a clear hypothesis
for their use, relevant preclinical data, and a
demonstrated use in well characterized groups of
patients

53. R e rec s
fe ne

54. REFERENCES
1. Goodman & Gilman’s The Pharmacological Basis
of THERAPEUTICS. Twelfth edition: pg 1731-
1740
2. Bertram G,Katzung,Basic & Clinical Pharmacology,
eleventh edition: pg 953-955.
3. Charles R.Craige, Robert E.Stitzel: MODERN
PHARMACOLOGY with Clinical applications.pg
653.
4. Lippincott’s Illustrated Reviews:Pharmacology 5th
edition:pg 509-511.

55. REVIEW ARTICLES
1. Amit Arora and Eric M: “Role of Tyrosine Kinase
Inhibitors in Cancer Therapy”, THE JOURNAL
OF PHARMACOLOGY AND EXPERIMENTAL
THERAPEUTICS [JPET] 315:971–979, 2005.
2. Jianming Zhang- “Targeting cancer with small
molecule kinase inhibitors”: Nature Rev. Drug
Discov January 2009 | Volume 9: 28-39.

59. Drug Interactions
Strong CYP3A4 Inhibitors
ketoconazole, itraconazole, voriconazole,
posiconazole
clarithromycin, telithromycin
atazanavir, indinavir, nelfinavir, ritonavir, saquinavir,
nefazodone
Moderate CYP3A4 Inhibitors
fluconazole, erythromycin, aprepitant, grapefruit
juice,
verapamil, cimetidine

60. Drug Interactions
• CYP3A4 Inducers
Barbiturates, carbamazepine, phenytoin
glucocorticoids
rifampin, rifabutin
nevirapine, efavirenz
troglitazone, pioglitozone
St. John’s Wort

61. ERLOTINIB
• Dosage adjustment
• Dosage adjustment for patients with
hepatic impairment
• None recommended → monitor for potential side
effects because of significant liver metabolism
• Dosage adjustment for patients with renal
impairment
• None recommended