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- 3. VEGFR-2 inhibitor • VEGFR-2 inhibitor, also known as (kinase insert domain receptor ----(KDR) inhibitor are tyrosine kinase receptor inhibitors • that reduce angiogenesis leading to anticancer activity.
- 4. Mechanism of receptor activation • This modification leads to the exposure of the ATP-binding site, which causes ATP binding on the receptor and also transphosphorylation on specific tyrosine residues. • They are Binding to VEGF receptor induces dimerization, which modifiestheconformation in the intracellular domain.
- 5. Mechansim of action • TKIs block the activity of tyrosine kinases and signaling pathway by binding at ATP binding site ATP binding site
- 6. SAR
- 8. MOA • Sorafenib is a protein kinase inhibitor with activity against many protein kinases ---------(Multi_kinase inhibitor)----------- • inhibits the VEGFR_2/PDGFR_B signaling cascade to inhibit angiogenesis ,tumer growth clinical uses • Sorafenib is indicated as Treatment of advanced renal cell cancer ,unresectable hepatocellular cancer ,thyroid cancer
- 9. • Metabolism------Liver oxidation and glucuronidation (CYP3A4 & UGT1A9-mediated) • Bioavailability -----38–49% • Protein binding-----99.5% • Elimination half-life-----25–48 hours • Excretion-------Feces (77%) and urine (19%) Pharmacokinetics
- 10. • cetylsalicylic acid The risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Sorafenib. • Albendazole The metabolism of Sorafenib can be increased when combined with Albendazole. • Amantadine The risk or severity of QTc prolongation can be increased when Sorafenib is combined with Amantadine interactions • Do not take with or immediately after a high- fat meal Take sorafenib at least 1 hour before or 2 hours after a high-fat meal, as sorafenib absorption can be reduced by a high-fat meal. • caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum levels Drug s foods
- 11. • Anaemia • Thrombocytopenia • Anorexia (weight loss) • Hypocalcaemia • Hypokalaemia • Depression side effects Very common (>10% ) • Alopecia (hair loss; occurs in roughly 30% of patients receiving sorafenib) • Lymphopenia,Nausea ,Vomiting Common (1-10%) Uncommon (0.1-1% ) • Hyperthyroidis m • Hyponatraemia • Dehydration
- 13. M.O.A • Include all receptors for platelet-derived growth factor (PDGF-Rs) and vascular endothelial growth factor receptors (VEGFRs), which play a role in both tumor angiogenesis and tumor cell proliferation. • The simultaneous inhibition of these targets therefore reduces tumor vascularization and triggers cancer cell apoptosis and thus results in tumor shrinkage. • that was approved by the FDA for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor • Sunitinib is being studied for treatment of meningioma which is associated with neurofibromatosis Clinical use
- 14. pharmacokinetic • Protein binding--- Binding of sunitinib and its primary metabolite to human plasma protein in vitro was 95% and 90%, respectively • Metabolism--- Sunitinib metabolized by CYP3A4 to an active N-desethyl metabolite • the terminal half-lives of sunitinib and its primary active metabolite are approximately 40 to 60 hours and 80 to 110 hours, respectively. • Absorption Maximum plasma concentrations (Cmax) of sunitinib are generally observed between 6 and 12 hours (Tmax) following oral administration. Food has no effect on the bioavailability of sunitinib. Sunitinib may be taken with or without food.
- 15. Side effects • Sunitinib adverse events are considered somewhat manageable and the incidence of serious adverse events low. • The most common adverse events associated with sunitinib therapy are fatigue, diarrhea, nausea, anorexia, hypertension Hand - foot syndrom black warning • Hepatotoxicity Hepatotoxicity may be severe, and in some cases, fatal; monitor hepatic function and interrupt, dose reduce, or discontinue as recommended
- 16. CONTRAINDICATION • Certain medications (e.g., sotalol, quinidine, thioridazine, chlorpromazine, pimozide, moxifloxacin, mefloquine, pentamidine, arsenic trioxide, tacrolimus) can increase the risk of a type of abnormal heart rhythm called QT prolongation, • and should not be used in combination with sunitinib
- 18. M.O.A • Lenvatenibe is one of Multikinases • Inhibiting VEGFR1 , VEGFR2 , and VEGFR3 . Lenvatinib also inhibits other RTKs clinical uses • differentiated thyroid cancer (DTC) • hepatocellular carcinoma (HCC) • renal cell carcinoma (RCC). Adverse Effects • Hypertension is the most common side effect of lenvatenibe , diarrhoea and fatigue
- 19. PHARMACOKINETIC • Lenvatinib is absorbed quickly from the gut, Bioavailability is estimated to be about 85% • Lenvatinib is metabolized by CYP3A4 to desmethyl- lenvatinib (M2). M2 and lenvatinib itself are oxidized by aldehyde oxidase (AO) . Another metabolite, also mediated by a CYP enzyme, is the N-oxide M3 Metabolism
- 21. M.O.A • Axitinib is a second generation tyrosine kinase inhibitor that works by selectively inhibiting vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3) • Through this mechanism of action, axitinib blocks angiogenesis, tumour growth and metastases • Used in kidney cell cancer clinical use Food Interactions • Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of axitinib
- 22. Metabolism • Axitinib undergoes mainly hepatic metabolism. • CYP450 , CYP3A4/5 are the main hepatic enzymes • while CYP1A2, CYP2C19, and uridine diphosphate glucuronosyltransferase (UGT1A1) enzymes are second • The two major human plasma metabolites, M7 (sulfoxide product) and M12 (glucuronide product), are considered pharmacologically inactive.
- 23. adverse effect decrease in appetite or ability to taste things hair loss heart burn joint or muscle pain constipation diarrhea, nausea ,vomiting
- 24. BEVASIZUMAB • Bivacizumab or Avastin ,the trade name ; is a humanized monoclonal antibody protein • Today , Avastin is already an essential component of cancer treatment with consistent survival increases demonstrated in multiple solid tumer
- 25. VEGF • The key mediator of the process of angiogenesis is vascular endothelial growth factor or VEGF for short • When VEGF binds to receptors on the surface of endothelial cells,it has been shown to exert important effects : 1-promoting tumer vessel survival 2-increasing tumer vessel permeability • 3-stimulating new tumer vessel growth ,VEGF is capable of new vascular sprouting within 1 day • And all of these effects increase oxygen and nutrients that feed tumer growth
- 26. M.O.A 1-regression of existing vessels -vascular regression is proceeded by loss of blood and lumin agency and as a result ,some tumer vessels may exsist for a short time with no blood flow before finally regressing -vascular tracks called basement membrane ghosts leave a fossil like record of where regressed tumer vessels once stood 2-normalization of survival vessels -endothelial fenestrations and intracellular gaps abnormalities that contribute to vessel permeability become closed off -these abnormalities promote the leakage of plasma proteins resulting in high pressure within the tumer that may restrict anti cancer drug delivery -so by reducing the pressure within the tumer vasculature,this normalizing effect my improve the delivery of chemotherapy within the tumer ,so Avastin can be combined with chemotherapy to maximize clinical outcomes 3-inhibition of new and recurrent vessels growth -Avastin may also continue to inhibit vascular sprouting ,new vasculature that's critical to continue tumer development
- 27. clinical uses • Avastin is commonly used to treat ovarian cervical, kidneys, brain, colon and lung cancers • Avastin may be used on its own as a single agent therapy but more often, it's combined with chemotherapy • Avastin is administered once every 2 to 3 weeks. • It's given as IV infusion , typically over 30 min, the first time you receive Avastin ,the doctor may prolong the infusion to 90 min to monitor and ensure you're not allergic to the medicine • First infusion: Infuse over 90 min • Second infusion: Infuse over 60 min if first infusion is tolerated • Subsequent infusions: Infuse over 30 min if second infusion over 60 min is tolerated • the half-life of Avastin is estimated to be 20 days. PHARMACOKINETICS
- 28. ADVERSE EFFECTS • Avastin is not a chemotherapy and therefore doesn't cause any of the usual effects of chemotherapy like hair loss ,weakened immunity, nausea,vomiting ,constipation , tiredness,.....etc. So most patients receiving Avastin as a single agent are well and feel almost normal • Less common but more serious adverse effects: 1-because it targets blood vessels ,it can cause bleeding 2-bowl perforation or fistulae which are abnormal communicating passages between organs 3-elevation of blood pressure , increase risk of heart attack , stroke and blood clots 4- Can cause proteinuria
- 29. CONTRAINDICATIONS • It's important not to become pregnant while on Avastin or to breastfeed while receiving Avastin
- 30. ﴿ اَم َو َُّرْصالن َّ الِإ َّْنِم َّ ِدنِع َّ ِ ّ للا َّ َعْال َِّ يز ِ ز َِّيمِكَحْال )