1. Podophyllotoxin (L01CB) Presented by : Mona Ahmed Sherif

2. . Plant alkaloids Tubulin inhibitors Vinca alkaloids Vinblastine vincristine vinorelbine vindesine Taxanes Paclitaxel Docetaxel Abraxane Topoisomerase inhibitors Podophyllotoxin Etoposide Teniposide Camptothecins Topotecan Irinotecan

3. Podophyllotoxin Has been primarily obtained from the American Mayapple (Podophyllum peltatum). Recently it has been discovered that a rare Himalayan Mayapple (Podophyllum hexandrum) contains it in a much greater quantity. Etoposide and Teniposide are semisynthetic derivatives of podophyllotoxin.

4. Mechanism Of Action Epipodophyllotoxin are cell cycle specific with activity in late S & G2 phase. Topoisomerase II creates and reseals double-stranded DNA breaks and therefore it is involved in DNA replication and repair. Epipodophyllotoxin inhibit topoisomerase II by stabilizing topoisomerase II -DNA complex &prevent the unwinding of DNA.

5. Mechanism Of Resistance 1. Multi-drug resistance phenotype with increased expression of glycoprotein resulting in enhanced drug efflux and reduced intracellular accumulation of drug. 2. Reduced expression of topoisomerase II enzyme. 3. Mutation of topoisomerase II with reduced binding affinity to the drugs.

7. Etoposide /Etoposide phosphate The water solubility of etoposide phosphate lessens the potential for precipitation following dilution and during intravenous administration. Following IV administration of etoposide phosphate, the drug is rapidly absorbed and completely converted to etoposide in plasma. Although in vitro cytotoxicity of etoposide phosphate is significantly less than that produced by etoposide, but once the salt form is dephosphorylated in vivo, its mechanism of action is equivalent to that of etoposide. Clinical studies directly comparing the pharmacokinetic parameters of etoposide and etoposide phosphate showed no statistically-significant difference in the etoposide plasma Cmax or AUC of the two formulations.

8. TeniposideEtoposide phosphateEtoposide Vumon, VM-26 EtopophosVipesid,VP-16 Trade name 50 mg (5 mL) amp100 mg vials to be reconstituted at conc of 10 mg/ml & 20 mg/ml 50 mg liquid-filled soft gelatin capsules. multiple-dose vials 100 mg/5 ml, 150 mg/7.5 ml, 500 mg/25 ml, 1000 mg/50 ml. Dosage forms Under refrigeration between 2 - 8 degree C, and keep in the original package to protect it from light. After mixing, do not refrigerate. Discard any unused liquid/solution. Do not save for later use. Storage Epipodophyllotoxin,topoisomerase II inhibitor Classification

9. Chemical & Physical Stabilities The chemical and physical stabilities of etoposide and teniposide have been investigated in different, commonly used, infusion fluids. It is concluded that etoposide and teniposide in 5% dextrose and 0.9% sodium chloride infusion fluids (concentration: 0.4 mg/mL) are chemically stable for at least 4 days at room temperature. Stability of the drugs is not influenced by the presence of normal room light nor by the type of container material used (glass bottles or polyvinyl chloride minibags). Occasional precipitation occurred in etoposide infusion fluids with a concentration higher than 0.4 mg/mL. Teniposide infusion solutions were physically stable at the tested concentrations up to 0.7 mg/mL.

10. TeniposideEtoposide phosphateEtoposide No oral form Following IV administration, it is rapidly absorbed and completely dephosphorylated in plasma to be activated to etoposide. The absolute bioavailability of the capsules averages 50%, with a range of 25% to 75%. Bioavailability >99% more protein- bound than etoposide (uptake and binding to cells is also greater). With increased fraction of free drug & higher incidence of toxicity 90-95 % Protein (mainly albumin) bounded Hypoalbuminemia result in increased fraction of free drug that increase incidence of toxicity Distribution Primarly in the liver (CYP2C19 )CYP2C19 4-12% excreted unchanged in urine Longer elimination half life ranges from 5 hr. Primarly in the liver (to less active metabolites) via (CYP3A4)CYP3A4 30-50 % excreted unchanged in urine. Elimination half life ranges from 1-3 hr. Metabolism

11. TeniposideEtoposide phosphateEtoposide No dose adjustment in renal impairment (except for significant dysfunction )is indicated. Dosage adjustment for hepatic failure is indicated. The risk of acute CNS depression and hypotension may be increased especially with higher doses of teniposide, probably because of the depressant effects of both the antiemetic and the alcohol present in the teniposide injection. Dose adjustment for renal dysfunction and hepatic failure are recommended. Use of higher (than recommended ) doses has been associated with hepatic toxicity and metabolic acidosis since the unbound fraction has been found to correlate significantly with bilirubin in a group of cancer patients. Dosage adjustment Salicylate, sulfamethizole, or tolbutamide cause small but significant displacement of etoposide / teniposide from plasma protein binding sites, which lead to substantial increases in free plasma concentrations of each and, possibly, increased there toxicity Drug interactions Phenytoin, phenobarbital :(via induction of hepatic microsomal enzyme -oxidation system ) increased teniposide cl by 2 to 3 fold, possibly resulting in decreased antineoplastic effect, so higher doses of teniposide may be required. Wafarin : Etoposide prolong PT &INR, altering anticoagulant effect of warfarin.Co administration require close monitoring of PT&INR & warfarin dose. Caution should be used when administering etoposide phosphate with drugs that inhibit phosphatase activities, such as levamisole hydrochloride(Ascaricides).

12. TeniposideEtoposide phosphateEtoposide 1.Refractory childhood acute lymphoblastic leukemia. 2.Non Hodgkin's Lymphoma. 3.Refractory neuroblastoma. 1.Germ cell tumor ( testicular & ovarian tumors ). 2.Small cell & Non small lung cancer 3.Hodgkin`s & Non Hodgkin's Lymphoma 4.Gasteric cancer 5.High dose therapy in transplant setting for various malignancies including (Brest cancer, Lymphoma & ovarian cancer ). Indication Linker Regimen; Treatment A (cycles 1,3,5&7) Daunorubocin Vincristine L-Asparginase Treatment B (cycles 2,4,6 & 8) Tenoposide Cytrabine Treatment C (cycle 9) Methotrexate Leucovorine In Lung cancer EP (Etoposide / Carboplatin) CAE (Cyclophosphamide / Doxorubicin / Etoposide ) PCE ( Paclitaxel / Carboplatin / Etoposide ) Protocol examples

13. Teniposide / Etoposide. Teniposide is less commonly used than etoposide. In teniposide, a thiophene group replaces the methyl group present on the glucose moiety of etoposide This alteration affects both the interaction with topoisomerase II and clinical pharmacology. Teniposide is more potent inhibiting topoisomerase II than etoposide. In addition, a greater fraction of teniposide is protein bound relative to etoposide. Renal function is less relevant to the clearance of teniposide than etoposide. Cremophor is used in teniposide formulations and may explain the greater frequency of hypersensitivity reactions observed with teniposide relative to etoposide.

14. Special Considerations In patient with abnormal renal function, dose reduction is recommended, Baseline serum creatinine should be obtained and dose should be reduced in proportion to changes in creatinine clearance. In patient with abnormal liver function, dose reduction is recommended, Baseline serum bilirubin (total) should be obtained, 25-50 % increase in serum bilirubin ………….. 50% of the usual dose, > 50% increase in serum bilirubin ………….…25% of the usual dose, If serum bilirubin > 3 mg/dl …………… alternative therapy should be used until liver function improved. To avoid hypotension, administrate the drug over a period of 30-60 minutes,if blood pressure drops, immediately discontinue therapy and administrate I.V fluid. Anaphylaxis's specially at initial infusion of therapy (probably due to the vehicle (Polysorbate 80 in Etoposide and Cremophore in Teniposide) may be fatal, so if hypersensitivity reaction is observed, immediately infusion should be stopped & antihistamine,steroid,h2blocker&pressor agent should be given. Carefully monitoring site of injection for signs of phlebitis, carefully avoid extravasations. Pregnancy category D.

15. Toxicity Myelosuppression (leucopenia more common than thrombocytopenia ). Nadir occur 10-14 days after intiation of thery with recovery by day 21. Mucositis &diarrhea Nausea &vomiting are mild to moderate, more common with oral form,could be reduced by informing patient to eat several small meals, avoid eating 2 hrs before therapy and limiting activities after therapy. Metalic taste during infusion Anorexia. Alopecia :occur in about 2/3 of the patients,sometimes progresses to total baldness,but reversible. Hypersensitivity reaction may be fata but less common,apppear as chills,fever,broncheospasm,dyspnea,tacchycardia,facial& tongue swelling hypo or hypertension. Local inflammation at injection site. Increased risk of secondary malignancies espicially AML typically developed withen 5-8 yrs of treatment.

16. Nadir Nadir basically means low point, however it refere to the blood counts, particularly white blood cell count and platelet count. Although these effects occur on normal cells that divide rapidly such as, the hair, the lining of the mouth, the cells lining the intestinal tract. The nadir time is usually about 10 days after treatment, although this may vary depending on the drugs given. The concern during the nadir time is that the body's first line of defense against infection, white blood cells (WBC) and the platelets, which help to clot the blood, are low leaving a person more susceptible to infection and bleeding. The next dose of chemotherapy is given only after a person's blood counts have left the nadir and recovered to a safe level.

17. Medical Considerations/Contraindications Etoposide and etoposide phosphate are contraindicated in patients who have demonstrated a previous hypersensitivity to etoposide or any components in the formulations. Etoposide/Teniposide medication should not be used when severe Leucopenia or severe Thrombocytopenia or bone marrow depression (dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively). Risk-benefit should be considered when the following medical problems exist:Chickenpox (existing or recent),Herpes zoster,risk of severe generalized disease. Down syndrome patients may be especially sensitive to the myelosuppressive effects of Teniposide; a 50% reduction in initial dosage is recommended pre-existing Infection recovery may be impaired; needs to be brought under control before initiation of Teniposide treatment due to risk of septicemia.