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  3. 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. 4. CATEGORIES OF PROTEIN KINASES• Classified into three different categories:1. Kinases that specifically phosphorylate tyrosine residues2. Kinases that phosphorylate serine and threonine residues, and3. Kinases with activity toward all three residues.
  5. 5. TYPES OF TYROSINE KINASES• Tyrosine kinases can be further subdivided into1. Receptor tyrosine kinases eg: EGFR, PDGFR, FGFR2. Non-receptor tyrosine kinases eg: SRC, ABL, FAK and Janus kinase
  6. 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. 7. RTK structure/function Regulatory domains
  8. 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. 9. TYROSINE KINASE INIBITORS1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 19. NILOTINIBToxicities• 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. 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. 21. Epidermal Growth Factor Receptor TyrosineKinase Inhibitors• Gefitinib,• Erlotinb• Lapatinib
  22. 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. 23. Epidermal Growth Factor Receptor TyrosineKinase Inhibitors• Pharmacokinetics of Gefitinib / ErlotinibAbsorption – 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 boundMetabolism – Predominantly via CYP3A4Elimination – Half life – Gefitinib- 48 hrs, Erlotinib- 36 hrs – Fecal 86%, renal elimination < 4%
  24. 24. GEFITINIB• Toxicities• Dermatologic – Rash, acne, xerosis, pruritus• Gastrointestinal – Diarrhea, Nausea, vomiting, anorexia• Ocular – Pain and corneal erosion/ulcer, aberrant eyelash growth
  25. 25. GEFITINIBToxicities• 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. 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. 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. 28. ERLOTINIBIt 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. 29. ERLOTINIBMechanism 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. 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. 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. 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. 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. 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. 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. 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. 37. LAPATINIB• ToxicitiesWhen combined with Capecitabine• Diarrhea• Palmar-plantar erythrodysesthesia• Nausea/vomiting• Rash• Fatigue• Decreases in LVEF• ECG changes
  38. 38. Vascular Endothelial GrowthFactor TyrosineKinase Inhibitors1. Semaxinib [with drawn]2. Vatalanib,3. Sunitinib,4. Sorafenib.
  39. 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. 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. 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. 42. SUNITINIB• Pharmacokinetics• Elimination – Primarily via feces (61%) – 16% renal elimination – Half life: Parent compound (40-60hrs), active metabolite (80-110hrs)
  43. 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. 44. SUNITINIB Toxicities• QT-prolongation• Left Ventricular Dysfunction• Hemorrhagic Events• Hypertension (30%)• Hypothyroidism – baseline thyroid function and monitor for signs
  45. 45. SUNITINIB Toxicities• Adrenal Insufficiency• GI distress – Diarrhea, nausea, vomiting, stomatitis, dyspepsia• Skin discoloration• Fatigue
  46. 46. SORAFENIBMechanism 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. 47. SORAFENIBPharmacokinetics• Absorption – Peak plasma levels achieved in ~3 hours – Food reduced bioavailability by ~29%• Distribution – Protein binding 99.5%
  48. 48. SORAFENIBPharmacokinetics• 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. 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. 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. 51. VATALANIB• It is being studied as a single agent and in combination with chemotherapy in patients with1. Colorectal cancer and liver metastases,2. Advanced prostate cancer3. Renal cell cancer4. Relapsed/refractory Glioblastoma multiforme.
  52. 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. 53. R e rec s fe ne
  54. 54. REFERENCES1. Goodman & Gilman’s The Pharmacological Basis of THERAPEUTICS. Twelfth edition: pg 1731- 17402. 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. 55. REVIEW ARTICLES1. 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.
  56. 56. Drug InteractionsStrong CYP3A4 Inhibitorsketoconazole, itraconazole, voriconazole, posiconazoleclarithromycin, telithromycinatazanavir, indinavir, nelfinavir, ritonavir, saquinavir,nefazodoneModerate CYP3A4 Inhibitorsfluconazole, erythromycin, aprepitant, grapefruit juice,verapamil, cimetidine
  57. 57. Drug Interactions• CYP3A4 InducersBarbiturates, carbamazepine, phenytoinglucocorticoidsrifampin, rifabutinnevirapine, efavirenztroglitazone, pioglitozoneSt. John’s Wort
  58. 58. 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