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2. TAMOXIFEN Sadia Alvi 2013-Mphil-2282 2 3. CONTENTS History Introducing Tamoxifen Approved Indications Pharmacokinetics Pharmacodynamics Effect of Drug on Body Systems Special Population Study 3 4. HISTORY Originally marketed as a an antifertility drug and developed in the cornerstone treatment for breast cancer. Approved by the FDA for postmenopausal metastatic breast cancer in 1977 4 5. INTRODUCING TAMOXIFEN General Use Breast cancer treatment and prevention Proper Name Tamoxifen Citrate Chemical Formula C26H29NO Chemical Type non-steroidal Selective Estrogen Receptor Modulator (SERM) Formulation Tamoxifen is a fine white powder and delivered orally in pill form 5 6. APPROVED INDICATIONS Indication Year of Approval Metastatic Breast Cancer (postmenopausal) 1977 Adjuvant Breast Cancer (postmenopausal, node-positive) 1986 Metastatic Breast Cancer (premenopausal) 1989 Adjuvant Breast Cancer (postoperative and/or chemotherapy treatment, postmenopausal, node-negative) 1990 Metastatic Breast Cancer (male) 1993 Reduction in Breast Cancer Incidence 1998 Ductal Carcinoma in Situ (DCIS) 2000 6 7. PHARMACOKINETICS Absorption Distribution Metabolism Excretion 7 8. ABSORPTION 20 mg Tamoxifen Oral Dose Cmax 40 ng/mL tmax 5 hours Terminal t1/2 5 -7 days Bioavailability 89% Steady State 1 dose/day 3 months 122 ng/mL 0 5 10 15 20 25 30 35 40 45 0 1 2 3 4 5 10 20 30 40 50 60 70 80 90 100 110 120 DrugConcentration(ng/mL) Time (h) 8 9. DISTRIBUTION Tamoxifen is 99% albumin-bound in serum Volume of Distribution 50 60 L/Kg This represents an extensive distribution to the peripheral tissues Areas of high concentration Breast Lung Liver Brain Bone Uterus http://www.sciencephoto.com/media/257869/enlarge 9 10. METABOLISM Tamoxifen undergoes first- pass metabolism Tamoxifen is metabolized by CYP enzymes CYP3A CYP2C9 CYP2D6 Tamoxifen undergoes enterohepatic circulation Prolongation of blood levels and fecal excretion Liver CYP-450 GI Tract Renal Excretion Tamoxifen Enterohepatic circulation Biliary Excretion 10 11. 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) 11 12. EXCRETION Primary route of elimination Biliary excretion 65% of administered drug is excreted slowly over a 2 week period Secondary route of elimination Renal excretion Less than 1% excreted via urine Excreted drug properties 70% are polar conjugates Indicates high level of metabolism 12 13. 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 13 14. 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 14 15. EFFECT OF DRUG ON BODY SYSTEMS Tamoxifen also binds and inhibits Protein Kinase C Regulates cell growth and differentiation Calmodulin Mediates process such as metabolism P-glycoproteins Efflux pump Ca2+ Channels Signal transduction Tamoxifen can target mutated cancer cells that lack ER Tamoxifen Cell membrane fluidity Calmodulin PKC DNA ER transcription Apoptosis x 15 16. 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 Vomiting http://alturl.com/9w7jy 16 17. EFFECT OF DRUG ON BODY SYSTEMS ADVERSE DRUG REACTIONS BENEFITS OF DRUG Increased risk of uterine cancer Agonist in uterine ER Increased cell proliferation Increased risk of blood clot formation Increase in clotting factors Increased risk of cataract Ophthalmic toxicities Reduced risk of breast cancer ER Antagonist Strengthens bones ER Agonist Lower risk of heart disease Increase HDL cholesterol Reduce LDL cholesterol 17 18. 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 19. SPECIAL POPULATION STUDY Brain cancer patients New Indication Treatment for malignant glioma 19 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 20 21. PHARMACOKINETICS Absorption Oral absorption through the portal vein into the liver Excretion Biliary system Metabolism First pass metabolism CYP 450 enzymes Distribution Tissues expressing ER, including the brain ADME 21 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 22 23. REFERENCES Avastin (bevacizumab) injection, solution [Genetech, Inc.]. US NLM, NIH, HHS. Revised 01/2007. Clinical Trials: Tamoxifen. US NLM, NIH, HHS. Fisher 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., and Wolmark 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 Cancer Institute. 90 (18). 1371-1388 Kleinsmith L.J., Kerrigan D., and Kelly J. 2010. Understanding cancer and related topics: understanding esrogen receptors, tamoxifen, and raloxifene. National Cancer Institute. The Merck Index. 13th Edition. Merck & Co., INC. Whitehouse Station, NJ. 2001. 23 24. REFERENCES 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. 4837-4844 Mackay H.J. and Twelves C.J. 2003. Protein kinase C: a target for anticancer drugs.Endocrine-Related Cancer. 10. 389-396 Fisher 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., and Wolmark 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 National Cancer Institute. 97 (22). 1652-1662 Nolvadex (tamoxifen citrate) Tablet [AstraZeneca Pharmaceuticals LP]. US NLM, NIH, HHS. Revised 01/2007. 24 25. REFERENCES Schroth 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 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 kinase C activity and insulin-like growth factor II expression in brain tumor cells. Journal of Neuro-Oncology. 67. 19-28 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 with chronic oral high-dose tamoxifen. Clinical Cancer Research. 2. 619-622 Mandlekar S. and Kong A.N.T. 2001. Mechanisms of Tamoxifen Induced apoptosis. Apoptosis. 6. 469-477. 25 26. 26 26 27. 27