Presentation on theme: "Tamoxifen Drug Interactions and Genomics Corey Engstrom PharmD Candidate 2010 Washington State University."— Presentation transcript:
Tamoxifen Drug Interactions and Genomics Corey Engstrom PharmD Candidate 2010 Washington State University
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
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
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 tumors hormone receptor status should be determined before deciding on treatment options for breast cancer (3)
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
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)
Adverse Reactions 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)
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 G 0 and G 1 phases; therefore, tamoxifen is cytostatic rather than cytocidal.
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
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, 4-hydroxy-N-desmethyltamoxifen (endoxifen) (22)
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 30-100 fold more than tamoxifen
Tamoxifen can be involved in DDIs either as a victim or as a perpetrator
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
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
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
CYP2D6 Inhibitors -SSRIs commonly used to treat hot flashes Selective serotonin reuptake inhibitors (SSRIs) –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)
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)
Tamoxifen As a Victim CYP3A4 Inhibitors It is theoretically possible that inhibitors of CYP3A4 will results in reduced concentration and effectiveness of endoxifen
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
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
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
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
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
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)
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
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
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
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)
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%
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.
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)
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
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