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