tyrosine kinase inhibitors
DESCRIPTION
Tyrosine Kinase InhibitorsTRANSCRIPT
TYROSINE KINASE INHIBITORS
PRESENTED BY:Y.VIJAY
FINAL YEAR POST GRADUATEDEPARTMENT OF PHARMACOLOGY
OSMANIA MEDICAL COLLEGE
CONTENTS
• INTRODUCTION• TYPES OF TYROSINE KINASES• ROLE OF KINASES IN SIGNALLING
PATHWAYS• DRUGS TARGETTING TYROSINE
KINASES• CONCLUSION • REFERECES
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.
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.
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
TK Intracellular Domain
Transmembrane Domain
Extracellular Domain
TYROSINE KINASE STRUCTURE
RTK structure/function
Regulatory domains
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
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.
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.
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
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)
IMATINIB MESYLATEDosing 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
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
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
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
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.
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
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)
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.
Epidermal Growth Factor Receptor TyrosineKinase Inhibitors
• Gefitinib,• Erlotinb• Lapatinib
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
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%
GEFITINIB
• Toxicities • Dermatologic
– Rash, acne, xerosis, pruritus • Gastrointestinal
– Diarrhea, Nausea, vomiting, anorexia • Ocular
– Pain and corneal erosion/ulcer, aberrant eyelash growth
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
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
GEFITINIBINDICATIONS
• 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
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
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
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%)
ERLOTINIBADVERSE 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
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.
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
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
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
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
LAPATINIB
• ToxicitiesWhen combined with Capecitabine• Diarrhea• Palmar-plantar erythrodysesthesia• Nausea/vomiting• Rash• Fatigue• Decreases in LVEF• ECG changes
Vascular Endothelial Growth Factor TyrosineKinase Inhibitors
1. Semaxinib [with drawn]
2. Vatalanib,
3. Sunitinib,
4. Sorafenib.
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
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
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.
SUNITINIB
• Pharmacokinetics• Elimination
– Primarily via feces (61%)– 16% renal elimination– Half life: Parent compound (40-60hrs), active
metabolite (80-110hrs)
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
SUNITINIB Toxicities
• QT-prolongation • Left Ventricular Dysfunction• Hemorrhagic Events• Hypertension (30%)• Hypothyroidism – baseline thyroid function and
monitor for signs
SUNITINIB Toxicities
• Adrenal Insufficiency• GI distress
– Diarrhea, nausea, vomiting, stomatitis, dyspepsia
• Skin discoloration• Fatigue
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
SORAFENIBPharmacokinetics• Absorption
– Peak plasma levels achieved in ~3 hours– Food reduced bioavailability by ~29%
• Distribution– Protein binding 99.5%
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
SORAFENIB Toxicities
• Hand-foot syndrome, alopecia, rash• Diarrhea or constipation• Nausea/vomiting, abdominal pain• Fatigue• High blood pressure• Bleeding• Neuropathy, joint pain• Dyspnea
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.
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.
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
References
REFERENCES1. 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.
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.
Drug InteractionsStrong CYP3A4 Inhibitorsketoconazole, itraconazole, voriconazole,
posiconazoleclarithromycin, telithromycinatazanavir, indinavir, nelfinavir, ritonavir, saquinavir, nefazodone
Moderate CYP3A4 Inhibitorsfluconazole, erythromycin, aprepitant, grapefruit
juice,verapamil, cimetidine
Drug Interactions
• CYP3A4 Inducers
Barbiturates, carbamazepine, phenytoin
glucocorticoids
rifampin, rifabutin
nevirapine, efavirenz
troglitazone, pioglitozone
St. John’s Wort
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