Drug Interactions in Breast Cancer Chemotherapy

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  • Background – statistics, treatment options
    Chemotherapy – polypharmacy & various drug used in breast cancer treatment
    Drug interactions – specific examples
    Pharmacogenomics – pipeline genotyping (2D6 & tamoxifen)
    GeneMedRx – the role of GeneMedRx
  • Prevalence among all cancer cases: Breast (31%), Lung (12%), Colon (11%)
    Incidence – 1.6million new cancers 2006. In women 679,510. Breast cancer (31%) = 210,000 new cases.
    Mortality – 273,560 female deaths. Breast cancer(26%) = 71,000 deaths
    Treatment options: surgery (lumpectomy, masectomy, double masectomy), radiation, chemotherapy – chemical therapy!
  • Chemotherapy agents
    Single/combo
    Stage of disease
    Different targets of cell cycle
    EFFECTIVE…but SEs!!!
    As you can see…. Many chemo drugs… BUT…more conditions….
  • Variations of drug interactions (chemo + chemo, chemo + other…) = can alter efficacy & toxicity profile.
  • Examples of drug interactions
    Not necessarily same mechanism (PK –vs- PD)
    Cyclo = effective anti-tumor; Aprepitant = potent anti-emetic
    Chemo & heart medications
  • Several resources
    Weak inducer/inhibitors
    Cyclo exception – moderate autoinducer
    Substrates – 3A4, pGP (efflux transporter – excrete drugs!)
    Trastuzumab – monoclonal antibody (degraded in tissues)
  • Chemotherapy interaction
    Common chemo combo = Paclitaxel + Doxorubicin
    Researchers looked at affect on each other
    Dox (48hrs)  Pac (24hrs), Pac  Dox (Cl reduced ~30%)
    Increased SE  granulocyte, stomatitis (mucositis)
  • Fairly large study
    Response:
    Time to disease progression (7.4 vs 4.6 months)
    Longer survival (25.1 vs 20.3 months) – f/u for 30months
    20% reduction in death risk
    BUT – increased cardiac dysfunction (x3 fold!!!)
    Generally responsive to treatment
  • DDI Mechanism
    Proposed mechanism – Her2/Neu receptors on myocardium (none!), Herceptin alone = no cardiac tox
    Prevailing theory - maybe Herceptin decreases cardiac cell repair time induced by Cy/Dox.
    Mechanism is currently unknown – BUT with GeneMedRx alert – MD can better manage.
    Mgmt
    risk:benefit assessment (age, history of cardiac dysfunction)
    Cardiac monitoring (EKG, ejection fraction)
  • Emetogenic potential = 90% will experience N/V
    Aprepitant…INHIBITOR!!!
    So.. Clinical trial looking at effect of aprepitant on cyclophos
  • SMALL STUDY
    Looked at Aprepitant effect Cyclo metabolism
    Aprepitant (one day prior, x4days, +3days post chemo) = 8days total
    While only ~5-7% reduction in enzyme activity and bioactivation - clinical relevance remains unclear.
    May seem insignif… but what about recurrent pts? Or lack of respsone?
    Knowledge of DDI…. Mgmt.
  • No adverse clinical effect noted
  • Currently no clinical trials
  • Mechanism: tamoxifen is only a weak 3A4 inhibitor, & R-warfarin affected only.
    Plasma binding proteins
    Albumin, α-glycoprotein
    Drugs bind, unbound drug is active
  • Mechanism: tamoxifen is only a weak 3A4 inhibitor, & R-warfarin affected only.
    Plasma binding proteins
    Albumin, α-glycoprotein
    Drugs bind, unbound drug is active
  • Adjuvant therapy – postoperative and/or with chemo
    Preventative therapy – only in high risk, due to risk of endometrial cancer, DVT/PE, stroke.
    ER agonist/antagonist
    SEs = hot flashes, night sweats
    METABOLISM….
  • TWO STEP METABOLIC PATHWAY!!!
    Endoxifen
    Knowing this … what do scientists like yourselves ask next?!?
  • At 12 years follow up: ~30% of *4/*4 had an event –VS- 60% of wt/wt.
  • PM > IM/PM (nearly 2x’s)
    At 12 years follow up: ~30% of *4/*4 had an event –VS- 60% of wt/wt.
    So, in SUMMARY…
  • A central source for PK/PD/PGX information….very useful for clinician.
  • PK/PD documented or potential intxns. Citation links.
  • PK/PD documented or potential intxns. Citation links.
  • PK/PD documented or potential intxns. Citation links.
  • PK/PD documented or potential intxns. Citation links.
  • Drug Interactions in Breast Cancer Chemotherapy

    1. 1. Drug Interactions in Breast Cancer Chemotherapy Sunshine S. Gascon University of Washington School of Pharmacy Doctoral Candidate, 2007 October 26, 2006
    2. 2. BREAST CANCER • Background • Chemotherapy • Drug interactions • Pharmacogenomics • GeneMedRx
    3. 3. BREAST CANCER Statistics1 • Most prevalent type in women (31%) • Median age – 40yo • Incidence – 210,000 new cases • Mortality – 71,000 women (33%) Treatment options • Surgery • Radiation therapy • Chemotherapy 1 American Cancer Society 2006 http://www.cancer.org/docroot/STT/content/STT_1x_Cancer_Facts__Figures_2006.asp
    4. 4. CHEMOTHERAPY POLYPHARMACY Chemotherapy Agents • Cyclophosphamide (Cytoxan) • Doxorubicin (Adriamycin) • Paclitaxel (Taxol) • Tamoxifen (Nolvadex) • Trastuzumab (Herceptin) Side effects • Nausea/vomiting – antiemetics (Zofran, Reglan, Emend) • Anemia – growth factors (Epogen, Procrit) • Immunocompromised – antibiotics, antifungals • Pain – opiod analgesics (hydrocodone, oxycodone)
    5. 5. CHEMOTHERAPY POLYPHARMACY Other Medical Conditions • Age related – birth control, menopause, osteoporosis • Arthritis – NSAIDS, etanercept (Enbrel) • Cardiovascular – hypertension, arrhythmias • Anticoagulants – warfarin • Endocrine – diabetes, hyperlipidemia • Epilepsy – phenytoin, carbamazepine • HIV/AIDS – NRTIs, PIs • SSRIs Chemotherapy regimens can be numerous, allowing for many potential adverse drug interactions.
    6. 6. DRUG INTERACTIONS CHEMO-RELATED DRUG CHEMO DRUG NON-CANCER RELATED DRUG Efficacy Toxicity
    7. 7. DRUG INTERACTIONS Chemo + Chemo • paclitaxel + doxorubicin = cardiotoxicity • trastuzumab + cyclo/dox = cardiotoxicity Chemo + Chemo-related • cyclophosphamide + aprepitant = ↓ chemo efficacy Chemo + Other • doxorubicin + digoxin = ↓ digoxin effects • tamoxifen + warfarin = ↑ warfarin effects
    8. 8. CHEMOTHERAPY METABOLISM Substrates Inducer Inhibitor Cyclophosphamide 2B6, 3A4 2C8, 2C9 2C19,2D6 2B6, 3A4, 2C8, 2C9 3A4 (weak) Doxorubicin 3A4 pGP, 2D6 2D6, 3A4 (weak) Paclitaxel 2C8, 3A4 pGP 2C8, 3A4 (weak) Tamoxifen 2D6, 3A4 2C8/9, pGP pGP, 3A4 (weak) Trastuzumab n/a Bold = major pathway Cozza et al. Drug Interaction Principles. 2003 ed Hansten & Horn. Top 100 Drug Interactions. 2006 ed Lexi-comp. Drug Information Handbook. 12th ed Scripture CD, Figg WD. Nature 2006(6);546-559.
    9. 9. DRUG INTERACTIONS Paclitaxel + Doxorubicin • Randomized, cross-over study in metastatic breast cancer patients2 n=10 Dox  Pac Pac  Dox Mean Diff Dox Cl (ml/min) 51 ± 16 34 ± 10 32% Dox Cmax (ng/ml) 26 ± 5 45 ± 8 70% Granulocyte counts 1.3/ul 0.2/ul Stomatitis (# patients) 1 7 • Paclitaxel given before doxorubicin decreases dox Cl • Leads to increased side effects (SEs) • Mechanism – PK interaction (3A4, pGP competition) • Mgmt – doxorubicin 24hrs prior to paclitaxel 2 Holmes et al. J Clin Oncol 1996 (14):2713-2721
    10. 10. DRUG INTERACTIONS Chemotherapy + Trastuzumab • Randomized, controlled, phase III clinical trial in metastatic breast cancer patients3 Cyclo/Dox (n=135) Cyclo/Dox + Trastuzumab (n=143) Response (%) 58 80 Cardiotox (%) 8 27 • Trastuzumab increased response – Longer time to disease progression (7.4 vs 4.6 months) – Longer survival time (25.1 vs 20.3 months) – Reduction in death risk (20%) • Increased cardiac dysfunction 3 Slamon et al. NEJM 2001 (344)11; 783-792.
    11. 11. DRUG INTERACTIONS Chemotherapy + Trastuzumab (cont’d) • Mechanism – Proposed: Her2 expression in cardiac tissues – Prevailing: Cyclo/Dox cause cardiac tissue damage, Trastuzumab impairs cellular repair time – Currently unknown PD interaction • Mgmt – Risk:benefit assessment – Cardiac monitoring (baseline, every three months) 3 Slamon et al. NEJM 2001 (344)11; 783-792.
    12. 12. DRUG INTERACTIONS Cyclophosphamide + Aprepitant • Cyclophosphamide4 – Effective anti-tumor agent – Prodrug bioactivation (via CYP3A4 to 4-OH-cyclophosphamide) – Autoinducer – High emetogenic potential • Aprepitant (Emend) – Effective for acute and delayed emesis – Dosing 1hr prior to several days post-chemo – CYP3A4 substrate, inhibitor (moderate) 4 de Jonge et al. Clinical Pharmacokinetics. 2005(44)11; 1135-1164
    13. 13. DRUG INTERACTIONS Cyclophosphamide + Aprepitant (cont’d) • Clinical trial5 – Co-administration (n=6) compared to reference group (n=49) – Measured cyclophosphamide & metabolite levels • Reduction in 4-OH-cyclophosphamide (5%) • Reduction in enzyme induction (7%) • Less nausea/vomiting with aprepitant (0.5 vs 4.8 days) • Mechanism – Aprepitant inhibits CYP3A4  decreased bioactivation of cyclophosphamide • Mgmt – Monitor for unexpected lack of anti-tumor response – Modify chemo regimen as necessary – Caution with use of other 3A4 inhibitors (antibiotics, antifungals) 5 de Jonge et al. Cancer Chemotherapy & Pharmacology 2005. 56(4):370-378
    14. 14. DRUG INTERACTIONS Chemotherapy + Digoxin • Chemotherapy – Inhibits growth of rapidly dividing cells – Affects epithelial cells, hair follicle cells – Alter GI mucosa lining  alter absorption • Digoxin – Effective use in heart failure, arrhythmias – Strengthens heart contractions – Therapeutic serum levels 0.8- to 2ng/ml
    15. 15. DRUG INTERACTIONS Chemotherapy + Digoxin (cont’d) • Clinical trial6 – Patients (n=6) receiving digoxin before & after chemotherapy. – Results: Digoxin AUC decreased by nearly 55% (31.8 –vs– 17.4 ng*hr/ml) • Mechanism – cytotoxic effects of chemotherapy alters GI absorption of digoxin. • Mgmt – Monitor for unexpected lack of response to digoxin – Monitor digoxin levels – Adjust digoxin dose accordingly 6 Bjornnson et al. Clin Pharmacol Ther. 1986 Jan;39(1):25-8
    16. 16. DRUG INTERACTIONS Tamoxifen + Warfarin • Tamoxifen – Selective estrogen receptor modulator (SERM) – Effect for breast cancer prevention & treatment – Metabolized primarily by CYP 2D6, 3A4 • Warfarin – Oral anticoagulant – Effective for stroke, DVT/PE prophylaxis – Narrow therapeutic window (usual INR 2-3) – Metabolized primarily by CYP 2C9, 3A4 Cozza et al. Drug Interaction Principles. 2003 ed
    17. 17. DRUG INTERACTIONS Tamoxifen + Warfarin (cont’d) • Clinical evidence – Several case reports – 65yo woman stabilized on warfarin (x11yrs)  increased PT time (required 40% dose reduction) – Woman stabilized on 25mg/d warfarin  subdural hematoma • Mechanism – Proposed mechanism: plasma protein-binding displacement warfarin – 99% bound tamoxifen – 99% bound • Management – Close PT/INR monitoring – Adjust warfarin dose accordingly Morello et al. Clinical Pharmacokinetics 2003. 42(4);361-372
    18. 18. DRUG INTERACTIONS Most drug interactions are manageable (monitoring, dose reduction, dose timing), indicating the importance of a central source for drug interaction information.
    19. 19. PHARMACOGENOMICS Tamoxifen and CYP2D6 • Tamoxifen – SERM (selective estrogen receptor modulator) – Estrogen receptor (ER) antagonist in breast  inhibits cell growth – Effective use in ER (+) tumors – Metabolism to active metabolite via CYP2D6 – SEs: menopausal symptoms (night sweats, hot flashes)
    20. 20. PHARMACOGENOMICS Tamoxifen and CYP2D6 (cont’d) ENDOXIFEN: • 100x receptor affinity • 100x potency • Effect of CYP2D6 polymorphisms on Tamoxifen response???
    21. 21. PHARMACOGENOMICS Tamoxifen and CYP2D6 (cont’d) • Clinical study7 – Breast cancer women (n=223) received tamoxifen (x5yrs) post-tumor removal – Genotyped for CYP2D6 • WT/WT (72.1%) – Extensive Metabolizer • WT/*4 (21.1%) – Intermediate metabolizer • *4/*4 ( 6.8 %) – Poor metabolizer – Endpoints • Disease-free time • Overall survival • Hot flashes 7 Goetz et al. Journal of Clinical Oncology 2005(23)36; 9312-9318
    22. 22. PHARMACOGENOMICS Tamoxifen and CYP2D6 (cont’d) • Clinical study8 – Results • CYP 2D6*4/*4 shown to have shorter time to disease recurrence • CYP 2D6*4/*4 genotypes did not experience hot flashes (non-*4/*4 had >20%) • Genetic variations in CYP2D6 alleles are associated with differences in clinical responses to treatment. • Knowledge of genotype may be helpful in choice of treatment regimens. HR (*4/*4:non) P Disease-free 1.86 0.089 Overall survival 1.12 0.780 8 Goetz et al. Journal of Clinical Oncology 2005(23)36; 9312-9318
    23. 23. GeneMedRx • Drug interactions database – Pharmacokinetic – Pharmacodynamic – Pharmacogenomic – Clincial evidence (trials, case-reports) – Potential drug interactions • Knowledge of drug interactions allows practitioners to: – Optimize patient’s medication management – Monitor efficacy and toxicity – Modify dose, administration, drug selection • Achieve goals: – Improve drug safety and efficacy – Improve patient response & quality of life
    24. 24. Thank You a BIG thanks to everyone at
    25. 25. QUESTIONS ???
    26. 26. References • American Cancer Society 2006 http://www.cancer.org/docroot/STT/content/STT_1x_Cancer_Facts__Figures_2006.asp • Baker AF, Dorr RT. Drug interactions with the taxanes: clinical implications. Cancer Treatment Reviews 2001(27); 221-233 • Bjornnson TD, Huang AT, Roth P, Jacob DS, Christenson R. Clinical Pharmacology & Therapeutics 1986. 39(1):25-28 • Cozza KL, Armstrong SC, Oesterheld JR. Drug Interaction Principles 2003. 2nd edition • De Jonge ME, Huitem AD, Holtkamp MJ, Van Dam SM, Beijnen JH, Rodenhuis S. Aprepitant inhibits cyclophosphamide bioactivation and thiotepa metabolism. Cancer Chemotherapy and Pharmacology 2005. 56(4); 370-378. • De Jonge ME, Huitema AD, Beijnen JH. Clinical pharmacokinetics of cyclophosphamide. Clinical Pharmacokinetics 2005. 44(11);1135-1164. • Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Visscher DW, Reynolds C, Couch FJ, Lingle WL, Flockhar DA, Desta Z, Perez EA, Ingle JN. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. Journal of Clinical Oncology 2005. 23(36); 9312-9318. • Hansten PD, Horn JR. Top 100 Drug Interactions 2006
    27. 27. References • Holmes FA, Madden T, Newman RA, Valero V, Theriault RL, Fraschini G, Walters RS, Booser DJ, Buzdar AU, Wiley J, Hortobagyi GN. Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer. Journal of Clinical Oncology 1996. 14(10); 2713-2721. • Lexi-comp. Drug Information Handbook 2003. 12th edition • Lodwick R, McConkey B, Brown AM. Life threatening interaction between tamoxifen and warfarin. British Journal of Medicine 1987. 295(6606);1141 • Morello KC, Wurz GT, DeGregorio MW. Pharmacokinetics of selective estrogen receptor modulators. Clinical Pharmacokinetics 2003. 42(4); 361-372 • Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga B, Norton L. Use of chemotherapy plus a monoclonal antibody against Her2 for metastatic breast cancer that overexpresses Her2. New England Journal of Medicine 2001. 344(11); 783-792. • Scripture CD, Figg WD. Drug interactions in cancer therapy. Nature 2006. (6);546-559.

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