Presentation on Tamoxifen; prevention and treatment for breast cancer. Prepared for Recent Trends in Therapeutics, CLIN 514, at Humber College, November 2011.

1. Tamoxifen
CLIN 514-01
RECENT TRENDS IN THERAPEUTICS
DR. PEIVAND PIROUZI
AVRIL PATRICK
MINA MEKHAIL

2. Agenda
Introducing Tamoxifen
Approved Indications
Pharmacokinetics
Pharmacodynamics
Effect of Drug on Body Systems
Pharmacogenomics
Special Population Study

3. 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)
Chemical Names
1-p-β-dimethyl-aminoethoxyphenyl-trans-1,2-diphenyl-1-one
(z)-2-[4-(1,2-Diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine
Formulation
Tamoxifen is a fine white powder and delivered orally in pill form

4. 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
1990
chemotherapy treatment, postmenopausal, node-negative)
Metastatic Breast Cancer (male) 1993
Reduction in Breast Cancer Incidence 1998
Ductal Carcinoma in Situ (DCIS) 2000

5. Pharmacokinetics
Absorption Distribution Metabolism Excretion

6. Absorption
45 20 mg Tamoxifen Oral Dose
40
Cmax 40 ng/mL
tmax 5 hours
35
Terminal t1/2 5 -7 days
Drug Concentration (ng/mL)
30
Bioavailability 89%
25
1 dose/day
20 Steady State 3 months
15 122 ng/mL
10
5
0
0 1 2 3 4 5 10 20 30 40 50 60 70 80 90 100 110 120
Time (h)

7. 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

8. Metabolism
 Tamoxifen undergoes Tamoxifen
first-pass metabolism
GI Tract
 Tamoxifen is metabolized
by CYP enzymes Enterohepatic
 CYP3A circulation
 CYP2C9
 CYP2D6 Liver
CYP-450
 Tamoxifen undergoes
enterohepatic circulation Renal Excretion
 Prolongation of blood levels
and fecal excretion Biliary
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 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

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. Pharmacodynamics
Tamoxifen and Invasive Breast Cancer  Breast Cancer Prevention
Prevention of At-Risk Women
Trial (1992)
 13, 388 at-risk women
 20 mg daily for 5 years
 Efficacy
 Invasive Breast Cancer
49% reduction
 Non-Invasive Breast
Cancer 50% reduction

14. Effect of Drug on Body Systems
 Tamoxifen also binds and Tamoxifen
inhibits
 Protein Kinase C Cell membrane fluidity
 Regulates cell growth and
differentiation PKC
 Calmodulin Calmodulin
 Mediates process such as ER
metabolism DNA x transcription
 P-glycoproteins
 Efflux pump
 Ca2+ Channels
 Signal transduction
Apoptosis
Tamoxifen 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
 Vomiting
http://alturl.com/9w7jy

16. Effect of Drug on Body Systems
Adverse Drug Reactions Benefits of Drug
 Increased risk of  Reduced risk of breast
uterine cancer cancer
 Agonist in uterine ER
 ER Antagonist
 Increased cell
proliferation  Strengthens bones
 Increased risk of blood  ER Agonist
clot formation
 Increase in clotting
 Lower risk of heart
factors disease
 Increased risk of  Increase HDL cholesterol
cataract  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 Tamoxifen’s
 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 patients
expressing extensive metabolism
http://alturl.com/6m6nc

19. Special Population Study
BRAIN 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
Absorption Distribution
Oral absorption through the Tissues expressing
portal vein into the liver ER, including the brain
ADME
Metabolism
Excretion
First pass metabolism
Biliary system
CYP 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 Design
Randomized Phase II Trial of Bevacizumab vs.
Title Tamoxifen for Treatment of Patients with Malignant
Glioma
Standard treatment as control, open label, randomized, parallel
Methodology
design
# of Subjects 60 subjects
Diagnosis and
Patients who have undergone surgery to remove malignant
main inclusion
glioma years 18 and older both male and female
criteria
Study Product, Tamoxifen, four (4) 40mg tablets/day, administered orally by the
Dose, Route,
subjects
Regimen
To determine whether Tamoxifen is an effective treatment vs.
Objective
Bevacizumab 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 specific
monoclonal antibody
 Reduction in brain tumor size
 Monitor via MRI or CT scan
 Side effects reduced compared to
standard treatment

25. References
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<http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=53695&CFID=68568765&CFTOKEN=c7cde62162e43be5-8E980C43-A853-F363-
B83B961222D86D50&jsessionid=ca301da0de303c387869>
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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
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Kleinsmith 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. 4837-4844
Mackay H.J. and Twelves C.J. 2003. Protein kinase C: a target for anticancer drugs.Endocrine-Related Cancer. 10. 389-396
Mandlekar 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. <http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=3420>
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with early stage breast cancer treated with tamoxifen. Journal of the American Medical Association. 302 (13). 1429-1436

26. Thank You
QUESTIONS?