1. Drug Interactions and Genomics
Tamoxifen
Drug Interactions and Genomics
Corey Engstrom
PharmD Candidate 2010
Washington State University

2. History
Originally marketed as a an antifertility drug and developed in the cornerstone treatment for breast cancer(1)
Approved by the FDA for postmenopausal metastatic breast cancer in 1977

3. Types of Treatment for Breast Cancers
Surgery
Radiation Therapy
Chemotherapy
Targeted therapy
Hormone Therapy
Aromatase inhibitor
e.g. Femara
Antiestrogens
e.g. fulvestrant
Selective Estrogen-Receptor Modifiers
e.g. tamoxifen

4. Hormonal Therapy
Between 50-80% of breast tumors have estrogen receptor (ER)-(4)
Studies have shown that tamoxifen is only effective in treating estrogen receptor-positive breast cancers. Therefore, the tumor’s hormone receptor status should be determined before deciding on treatment options for breast cancer(3)

5. FDA Approved Indications
Adjuvant treatment for breast cancer
Breast cancer, High-risk; Prophylaxis
Malignant neoplasm of male breast, Metastatic
Metastatic breast cancer
Intraductal carcinoma in situ of breast

6. Duration of Therapy
Studies have confirmed the benefit of taking adjuvant tamoxifen daily for 5 years. When taken for 5 years, tamoxifen reduces the chance of the original breast cancer coming back in the same breast or elsewhere. It also reduces the risk of developing a second primary cancer in the other breast(3)

7. Adverse Reactions Cardiovascular: Flushing (33% to 41%)
Endocrine metabolic: Hot flashes (3% to 80%), fluid retention (32%) hypertriglyceridemia
Neurologic: Weakness (19%), depression (>2%)
Cardiovascular: Flushing (33% to 41%)
[U.S. Boxed Warning]: 3-fold increased incidence of uterine or endometrial cancers
[U.S. Boxed Warning]: Serious and life-threatening events, including stroke and pulmonary emboli (1% per year)

8. Mechanism of Action
Competitively binds to estrogen receptors on tumors and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects
Nonsteroidal agent with potent antiestrogenic properties which compete with estrogen for binding sites in breast and other tissues
Cells accumulate in the G0 and G1 phases; therefore, tamoxifen is cytostatic rather than cytocidal.

9. Pharmacokinetics of Tamoxifen
Substrates
Major pathways
CYP2D6, CYP3A4
Minor pathway
CYP2C9, CYP2B6, CYP2C19, FMO3 CYP2E1,UGT2B7, UGT1A10, CYP2C8, UGT1A4, UGT1A8, SULT1A1, CYP2A6
Pathways of inhibition
carboxylesterase 1
ABCB1-P-gp
UGT2B7
CYP3A4
ABCG2-BCRP
CYP2C9
Transporters
ABCB1
ABCC1
ABCG2

10. Primary Metabolites
Tamoxifen is a prodrug that is metabolized to its (major) primary metabolites:(21)
N-desmethyltamoxifen
Principally formed by CYP3A4 (and CYP3A5)
4-hydroxytamoxifen
Principally formed by CYP2D6
Active metabolite
Found in reduced concentrations as compared to endoxifen
Oxidation of these metabolites results in the formation of the abundant and pharmacologically active metabolite, hydroxy-N-desmethyltamoxifen (endoxifen)(22)

11. Active Metabolite Endoxifen
Main active metabolite of tamoxifen is endoxifen
Endoxifen plasma concentrations are around 5–10 fold higher than those of 4-hydroxytamoxifen(10)
Endoxifen is converted from the primary metabolites via two routes
CYP2D6
CYP3A4
Endoxifen has a binding affinity to the target receptor that is fold more than tamoxifen

13. Tamoxifen can be involved in DDIs either as a victim or as a perpetrator

14. DDIs:Tamoxifen as a victim
As a victim, if endoxifen is reduced, the oncologic effects may be diminished
2 major routes by which this may occur:
CYP2D6 inhibitors can block formation of endoxifen from N-desmethylTMF
CYP3A4 inhibitors can block formation of endoxifen from 4-OH TMF
CYP3A4 inducers may increase the concentration of endoxifen and decrease concentration of 4-OHTMF

15. DDIs: Tamoxifen as a perpetrator
As a perpetrator, it can change the AUC and possibly the effects of the victim drug
S-warfarin thru inhibition of CYP2C9
Losartan thru inhibition of CYP2C9
Letrozole thru unknown mechanism

16. Tamoxifen As a Victim- CYP2D6 Inhibitors
Since tamoxifen is not clinically active against tumor cells without CYP2D6 converting it to endoxifen, there can be a significant decrease in endoxifen plasma levels when administered with other drugs that prevent tamoxifen from converting to endoxifen; therefore, tamoxifen may be less effective at preventing tumor growth if given with CYP2D6 inhibitors

17. Examples of Potent 2D6 Inhibitors
CYP2D6 Inhibitors
SSRI’s
Paroxetine (established)
Fluoxetine (conflicting evidence)
Other Antidepressants
Bupropion (theoretical)
Quinidine (theoretical)
Terbinafine (theoretical)

18. CYP2D6 Inhibitors -SSRIs commonly used to treat hot flashes
Selective serotonin reuptake inhibitors (SSRI’s)
The use of paroxetine is associated with an increased risk of death from breast cancer use during tamoxifen treatment (5)
A review cited two observational studies finding that women who took fluoxetine or sertraline with tamoxifen had a higher 2-year recurrence rate (13.9% vs. 7.5%) of breast cancer(7)
However there is conflicting evidence   
2 studies found no association between cancer recurrence and use of CYP2D6 inhibiting SSRIs(7)

19. Alternative Antidepressants
Citalopram (Celexa)
may be a safer alternative when choosing an SSRI with Tamoxifen since it is a less potent CYP2D6 inhibitor(6)  
Venlafaxine (Effexor)
2 studies found no change in endoxifen levels(17)(19)

20. Tamoxifen As a Victim CYP3A4 Inhibitors
It is theoretically possible that inhibitors of CYP3A4 will results in reduced concentration and effectiveness of endoxifen

21. Tamoxifen as victim: CYP3A4 Inducers
Since tamoxifen is metabolized by CYP3A4, drugs that induce the metabolism of tamoxifen will decrease to amount of parent compound and increase the conversion to the active metabolite (endoxifen); therefore, the effectiveness of endoxifen could be increased if given concomitantly with CYP3A4 inducers

22. Caveat
Endoxifen is glucoronidated by UGT2B7 and UGT1A8; therefore, whether endoxifen levels increase or decrease with a CYP3A4 inducer drug depends on whether the CYP3A4 inducer is also an inducer of UGT2B7 or UGT1A8
For example:
If drug x is not a CYP3A4 inducer but is a UGT2B7 or UGT1A8 inducer
Decrease in endoxifen level, but tamoxifen is unaffected
If drug x is a CYP3A4 inducer and a UGT inducer
Tamoxifen will decrease
Endoxifen levels will be a balance between:
The amount of increased conversion from tamoxifen leading to increased endoxifen levels
The amount of increase in metabolism of endoxifen leading to decreased endoxifen levels

23. Tamoxifen as victim: CYP3A4 Inducers
Rifampin and Tamoxifen(4)
In a clinical study, tamoxifen Cmax was decreased 55%  and the AUC was decreased 86% when rifampin was taken concurrently
An intermediate metabolite, N-desmethyltamoxifen, had a 62% reduction in its AUC
The effect on endoxifen is not known

24. Tamoxifen as victim: CYP3A4 Inducers
Bexarotene and Tamoxifen(2)
Concomitant administration of bexarotene and tamoxifen resulted in approximately a 35% decrease in plasma concentrations of tamoxifen
MOA
*possibly through an induction CYP3A4

25. Tamoxifen as victim:CYP3A4 Inducers
Aminoglutethimide and Tamoxifen(2)
A clinical study reported a 3-fold increase in tamoxifen clearance resulting in a decrease in tamoxifen AUC of 73% when the medications were administered concomitantly for 6 weeks.
reduces both tamoxifen and endoxifen plasma concentrations
Medroxyprogesterone Acetate
reduces plasma concentrations of endoxifen, but not tamoxifen (2)
Clinical effect is unknown
Inducer of 3A4
Possible UGT inducer

26. Tamoxifen as a perpetrator
Letrozole
Tamoxifen reduced the plasma concentration of letrozole by 37% when these drugs were co-administered(2)
Losartan
Increased losartan/E3174 (an active losartan metabolite) ratio (0.73 to 1.66) as a result of CYP2C9 inhibition by tamoxifen
less losartan active metabolite and decreased efficacy(12)
Warfarin
When concurrent therapy with tamoxifen and warfarin is utilized, the combination may significantly increase the anticoagulant effect of warfarin leading to risk of bleeding:due to CYP2C9 inhibition (12)

27. Genotyping for CYP2D6 There are four types of CYP2D6 metabolizers
Poor Metabolizers (PMs)
Individuals with 2 alleles that have no CYP2D6 activity
Intermediate metabolizers (IMs)
Individuals with 2 alleles with reduces activity
Individuals with 1 allele that has reduced activity and 1 allele with no activity
Extensive “normal” Metabolizers (EMs)
Individuals with 1 or 2 alleles that function normally
Ultraextensive metabolizers (UEMs)
Individuals with 3 or more alleles and have unusually high CYP2D6 activity

28. Poor Metabolizers of CYP2D6
Effect of PMs on tamoxifen
Leads to a decrease in endoxifen levels and increase in tamoxifen levels
Decrease in efficacy
Increase in toxicity
CYP2D6*4
Nonfunctioning allele
A study showed patients that were homozygous had(13)
Shorter relapse-free time
Worse disease-free survival
A clinical trial showed that tamoxifen used to prevent breast cancer is less likely to be beneficial for healthy woman that are homozygous for CYP2D6*4(14)
There are conflicting studies(16)
_ Also shown for other non-functioning alleles

29. Intermediate metabolizers of CYP2D6
Effect of IMs on tamoxifen
Better outcomes than PM, but still leads to reduced efficacy
Study showed that women taking tamoxifen that were IMs had better outcomes than poor metabolizers (15)
IMs includes EMs that were taking a CYP2D6 inhibitor concomitantly

30. Extensive or normal Metabolizers of CYP2D6
Effect of EMs on tamoxifen
Individuals should have normal levels of tamoxifen unless taken with CYP2D6 inhibitor
Study showed that the best outcomes of tamoxifen use came from EMs that were not taking CYP2D6 inhibitors(15)

31. Ultraextensive metabolizers of CYP2D6
Effect of UMs on tamoxifen
Has the potential for endoxifen levels to lead to increased concentration of endoxifen and therefore better outcomes or toxicity
Varies in different populations
Caucasian American 4%
Saudi Arabians
21%
Ethiopians
29%

32. Hoskins 2010

33. FDA Recommendations
In October 2006, the FDA recommended that the tamoxifen prescribing information be updated to include information about CYP2D6 genotypes, CYP2D6 genotyping tests, and the potential relationship between CYP2D6 genotype and clinical outcome.
Members of the Endocrinologic and Metabolic Drugs Advisory Committee have not reached a consensus as to whether testing should be recommended or considered as an option.

34. Tamoxifen and CYP2C19 CYP2C19*17
A study suggests that this may be an UM phenotype
Patients with tamoxifen, there are reduced breast cancer recurrences and prolonged relapse-free time and event-free survival rates (23)
Another study found that carriers of CYP2C19*17 allele had less frequent recurrences following tamoxifen when compared with non CYP2C19*17 carriers(24)

35. Why Should Patients Taking Tamoxifen Have A Genotype Screening For CYP2D6 and CYP2C19*17?
May help to determine:
effectiveness of tamoxifen
35% of women with advanced ER positive cancer do not respond to tamoxifen(17)
Genetic variation- CYP2D6 PMs (18)
_ Genetic variation-CYP2C19*17 have better outcomes
- Genetic variation-CYP2D6 UM may have better outcomes
Alternative to monitoring initial plasma levels
Steady-state metabolite concentrations are not reached until after a month of continuous therapy(20)
Genotyping can rapidly determine metabolizer type
toxicity
CYP2D6 UMs may lead to excessive endoxifen-
drug interactions
Different types of metabolizers may be more or less affected by taking CYP2D6 inhibitors concomitantly ; e.g., CYP2D6 IMs

36. References
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37. References
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