1. TamoxifenCLIN 514-01RECENT TRENDS IN THERAPEUTICS DR. PEIVAND PIROUZIAVRIL PATRICKMINA MEKHAIL

2. AgendaIntroducing Tamoxifen Approved IndicationsPharmacokineticsPharmacodynamicsEffect of Drug on Body Systems PharmacogenomicsSpecial Population Study 3. Introducing TamoxifenGeneral UseBreast cancer treatmentand preventionProper NameTamoxifen CitrateChemical FormulaC26H29NOChemical Typenon-steroidal Selective Estrogen Receptor Modulator (SERM)Chemical Names1-p--dimethyl-aminoethoxyphenyl-trans-1,2-diphenyl-1-one(z)-2-[4-(1,2-Diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamineFormulationTamoxifen is a fine white powder and delivered orally in pill form 4. Approved IndicationsIndication Year of ApprovalMetastatic Breast Cancer (postmenopausal) 1977Adjuvant Breast Cancer (postmenopausal, node-positive)1986Metastatic Breast Cancer (premenopausal)1989Adjuvant Breast Cancer (postoperative and/or1990chemotherapy treatment, postmenopausal, node-negative)Metastatic Breast Cancer (male) 1993Reduction in Breast Cancer Incidence1998Ductal Carcinoma in Situ (DCIS) 2000 5. PharmacokineticsAbsorption Distribution Metabolism Excretion 6. Absorption 4520 mg Tamoxifen Oral Dose 40Cmax40 ng/mLtmax 5 hours 35 Terminal t1/2 5 -7 daysDrug Concentration (ng/mL) 30 Bioavailability89% 251 dose/day 20 Steady State 3 months 15 122 ng/mL 105 00 1 2 3 4 5 10 20 30 40 50 607080 90 100110 120 Time (h) 7. Distribution Tamoxifen is 99% albumin-bound in serum Volume of Distribution 50 60 L/Kg This represents an extensivedistribution to the peripheraltissues Areas of high concentration Breast Lung Liver Brain Bone Uterushttp://www.sciencephoto.com/media/257869/enlarge 8. Metabolism Tamoxifen undergoesTamoxifenfirst-pass metabolismGI Tract Tamoxifen is metabolizedby CYP enzymesEnterohepatic CYP3A circulation CYP2C9 CYP2D6Liver CYP-450 Tamoxifen undergoes enterohepatic circulation Renal Excretion Prolongation of blood levels and fecal excretionBiliary Excretion 9. Metabolism Extensive metabolism following absorption Demethylation Hydroxylation Conjugation 3 major metabolites are produced N-desmethyl tamoxifen 4-hydroxy tamoxifen 4-hydroxy-N-desmethyl tamoxifen (endoxifen) 10. Excretion Primary route of elimination Biliary excretion 65% of administered drug is excreted slowly over a 2 weekperiod Secondary route of elimination Renal excretion Less than 1% excreted via urine Excreted drug properties 70% are polar conjugates Indicates high level of metabolism 11. Pharmacodynamics Estrogen receptors (ER)exist in different tissues Breast, brain, lung, liver, bone,uterus Normal Cellular Function Estrogen binds to ER Transcription factor synthesis Cell proliferation 12. Pharmacodynamics Selective Estrogen Receptor Modulator (SERM) A drug that targets estrogen receptors in specific tissues How Tamoxifen Works Antagonist in breast and brain No transcription Cell growth arrest/apoptosis Agonist in lung, liver, bone, and uterus Normal function 13. PharmacodynamicsTamoxifen and Invasive Breast Cancer Breast Cancer Prevention Prevention of At-Risk WomenTrial (1992) 13, 388 at-risk women 20 mg daily for 5 years Efficacy Invasive Breast Cancer49% reduction Non-Invasive BreastCancer 50% reduction 14. Effect of Drug on Body Systems Tamoxifen also binds and Tamoxifen inhibits Protein Kinase CCell membrane fluidity Regulates cell growth and differentiationPKC Calmodulin Calmodulin Mediates process such asER metabolism DNA x transcription P-glycoproteins Efflux pump Ca2+ Channels Signal transductionApoptosisTamoxifen can target mutated cancer cells that lack ER 15. Effect of Drug on Body Systems Most common side effects (up to 25% occurrence) Rarely severe enough to require discontinuation of treatment Hot flashes Nausea Vomitinghttp://alturl.com/9w7jy 16. Effect of Drug on Body Systems Adverse Drug ReactionsBenefits of Drug Increased risk of Reduced risk of breastuterine cancer cancer Agonist in uterine ER ER Antagonist Increased cellproliferation Strengthens bones Increased risk of blood ER Agonistclot formation Increase in clotting Lower risk of heartfactorsdisease Increased risk of Increase HDL cholesterolcataract Reduce LDL cholesterol Ophthalmic toxicities 17. Effect of Drug on Body Systems Drug-Drug Interactions Coumarin-type anticoagulants (Warfarin) Both 99% bound to albumin Tamoxifen has a higher affinity for albumin Co-administration results in a risk of Warfarin over dose Rifampin (TB Antibiotic) CYP 34A inducer Reduces Tamoxifens Bioavailability by 86% Cmax by 55% Prozac (Anti-depressant) CYP 2D6 competitor Decreases the effect of Tamoxifen http://alturl.com/apbr2 18. Pharmacogenomics Genetic risk of breast cancer BRCA1 & BRCA2 gene mutations CYP 2D6 polymorphisms Tamoxifen is metabolized primarily by CYP 2D6 Multiple alleles for the CYP 2D6 gene Extensive metabolizers Poor metabolizers Improved clinical outcomes in patientsexpressing extensive metabolismhttp://alturl.com/6m6nc 19. Special Population StudyBRAIN CANCER PATIENTS New Indication Treatment for malignant glioma 20. About the Population Rational for Special Population High level of cell proliferation in brain Brain cells contain estrogen receptors Proliferative signal transduction in glioma cells has been shown to occur through a predominantly Protein Kinase C dependent pathway P-glycoprotein functions as a transporter in the blood-brain barrier 21. Pharmacokinetics AbsorptionDistributionOral absorption through theTissues expressing portal vein into the liverER, including the brainADMEMetabolismExcretionFirst pass metabolism Biliary systemCYP 450 enzymes 22. Pharmacodynamics Tamoxifen is an ER antagonist in the brain Prevents transcription Cell growth arrest/apoptosis Tamoxifen is the only PKC inhibitor small enough to cross the blood-brain barrier Inhibits signal transduction Cell growth arrest/apoptosis Tamoxifen inhibits P-glycoprotein function Increased bioavailability of Tamoxifen 23. Study DesignRandomized Phase II Trial of Bevacizumab vs.Title Tamoxifen for Treatment of Patients with MalignantGliomaStandard treatment as control, open label, randomized, parallelMethodologydesign# of Subjects 60 subjectsDiagnosis and Patients who have undergone surgery to remove malignantmain inclusion glioma years 18 and older both male and femalecriteriaStudy Product, Tamoxifen, four (4) 40mg tablets/day, administered orally by theDose, Route, subjectsRegimenTo determine whether Tamoxifen is an effective treatment vs.ObjectiveBevacizumab for malignant gliomas 24. Hypothesis Decreased PKC activity Monitorer by Enzyme Linked Immunoabsorbent Assay(ELISA) Inhibition of P-glycoproteins Analysis by flow cytometery using P-glycoprotein specificmonoclonal antibody Reduction in brain tumor size Monitor via MRI or CT scan Side effects reduced compared to standard treatment 25. ReferencesAvastin (bevacizumab) injection, solution [Genetech, Inc.]. US NLM, NIH, HHS. Revised 01/2007.Clinical Trials: Tamoxifen. US NLM, NIH, HHS. Couldwell W.T., Hinton D.R., Surnock A.A., DeGiorgio C.M., Weiner L.P., Apuzzo M.L.J., Masri L., Law R.E., and Weiss M.H. 1996. Treatment of recurrent malignant gliomas withchronic oral high-dose tamoxifen. Clinical Cancer Research. 2. 619-622Fisher B., Costantino J.P., Wickerham D.L., Redmond C.K., Kavanah M., Cronin W.M., Vogel V., Robidoux A., Dimitrov N., Atkins J., Daly M., Wieand S., Chiu E.T., Ford L., andWolmark N. 1998. Tamoxifen for prevention of breast cancer: report of the national surgical adjuvant breast and bowel project p-1 study. Journal of the National CancerInstitute. 90 (18). 1371-1388Fisher B., Costantino J.P., Wickerham D.L., Cecchini R.S., Cronin W.M., Robidoux A., Bevers T.B., Kavanah M.T., Atkins J.N., Margolese R.G., Runowicz C.D., James J.M., Ford L.G., andWolmark N. 2005. Tamoxifen for the prevention of breast cancer: current status of the national surgical adjuvant breast and bowel project P-1 study. Journal of the NationalCancer Institute. 97 (22). 1652-1662Kleinsmith L.J., Kerrigan D., and Kelly J. 2010. Understanding cancer and related topics: understanding esrogen receptors, tamoxifen, and raloxifene. National Cancer Institute.Lien E.A., Solheim E., and Ueland P.M. 1991. Distribution of tamoxifen and its metabolites in rat and human tissues during steady-state treatment. Cancer Research. 51. 4837-4844Mackay H.J. and Twelves C.J. 2003. Protein kinase C: a target for anticancer drugs.Endocrine-Related Cancer. 10. 389-396Mandlekar S. and Kong A.N.T. 2001. Mechanisms of Tamoxifen Induced apoptosis. Apoptosis. 6. 469-477.The Merck Index. 13th Edition. Merck & Co., INC. Whitehouse Station, NJ. 2001.Nolvadex (tamoxifen citrate) Tablet [AstraZeneca Pharmaceuticals LP]. US NLM, NIH, HHS. Revised 01/2007. Ramachandran C., Khatib Z., Pefkarou A., Fort J., Fonseca H.B., Melnick S.J., and Escalion E. 2004. Tamoxifen modulation of etoposide sytotoxicity involves inhibition of protein kinaseC activity and insulin-like growth factor II expression in brain tumor cells. Journal of Neuro-Oncology. 67. 19-28Schroth W., Goetz M.P., Hamann U., Fasching P.A., Schmidt M., Winter S., Fritz P., Simon W., Suman V.J., Ames M.M., Safgren S.L., Kuffel M.J., Ulmer H.U., Strick R., Beckmann M.W., Koelbl H., Weinshilboum R.M., Ingle J.N., Eichelbaum M., Schwab M., and Brauch H. 2009. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. Journal of the American Medical Association. 302 (13). 1429-1436 26. Thank You QUESTIONS?