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Drug Interactions in Breast Cancer Chemotherapy

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1 Drug Interactions in Breast Cancer Chemotherapy
Sunshine S. Gascon University of Washington School of Pharmacy Doctoral Candidate, 2007 October 26, 2006

2 BREAST CANCER Background Chemotherapy Drug interactions
Pharmacogenomics GeneMedRx 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

3 BREAST CANCER Statistics1 Treatment options
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 Prevalence among all cancer cases: Breast (31%), Lung (12%), Colon (11%) Incidence – 1.6million new cancers 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! 1American Cancer Society 2006

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) 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….

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.

DRUG INTERACTIONS CHEMO DRUG Efficacy Toxicity Variations of drug interactions (chemo + chemo, chemo + other…) = can alter efficacy & toxicity profile. CHEMO-RELATED DRUG NON-CANCER RELATED DRUG

7 DRUG INTERACTIONS Chemo + Chemo Chemo + Chemo-related Chemo + Other
paclitaxel + doxorubicin = cardiotoxicity trastuzumab + cyclo/dox = cardiotoxicity Chemo + Chemo-related cyclophosphamide + aprepitant = ↓ chemo efficacy Chemo + Other doxorubicin + digoxin = ↓ digoxin effects tamoxifen + warfarin = ↑ warfarin effects Examples of drug interactions Not necessarily same mechanism (PK –vs- PD) Cyclo = effective anti-tumor; Aprepitant = potent anti-emetic Chemo & heart medications

Substrates Inducer Inhibitor Cyclophosphamide 2B6, 3A4 2C8, 2C9 2C19,2D6 2B6, 3A4, 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 Several resources Weak inducer/inhibitors Cyclo exception – moderate autoinducer Substrates – 3A4, pGP (efflux transporter – excrete drugs!) Trastuzumab – monoclonal antibody (degraded in tissues) Bold = major pathway Cozza et al. Drug Interaction Principles ed Hansten & Horn. Top 100 Drug Interactions ed Lexi-comp. Drug Information Handbook. 12th ed Scripture CD, Figg WD. Nature 2006(6);

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 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) 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 2Holmes et al. J Clin Oncol 1996 (14):

10 Cyclo/Dox + Trastuzumab
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 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 3Slamon et al. NEJM 2001 (344)11;

11 DRUG INTERACTIONS Chemotherapy + Trastuzumab (cont’d) Mechanism Mgmt
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) 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) 3Slamon et al. NEJM 2001 (344)11;

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) Emetogenic potential = 90% will experience N/V Aprepitant…INHIBITOR!!! So.. Clinical trial looking at effect of aprepitant on cyclophos 4de Jonge et al. Clinical Pharmacokinetics. 2005(44)11;

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) 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. 5de Jonge et al. Cancer Chemotherapy & Pharmacology (4):

14 DRUG INTERACTIONS Chemotherapy + Digoxin Chemotherapy Digoxin
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 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 No adverse clinical effect noted 6Bjornnson et al. Clin Pharmacol Ther Jan;39(1):25-8

16 DRUG INTERACTIONS Tamoxifen + Warfarin Tamoxifen Warfarin
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 Currently no clinical trials Cozza et al. Drug Interaction Principles ed

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 Mechanism: tamoxifen is only a weak 3A4 inhibitor, & R-warfarin affected only. Plasma binding proteins Albumin, α-glycoprotein Drugs bind, unbound drug is active Morello et al. Clinical Pharmacokinetics (4);

18 DRUG INTERACTIONS Most drug interactions are manageable (monitoring, dose reduction, dose timing), indicating the importance of a central source for drug interaction information. Mechanism: tamoxifen is only a weak 3A4 inhibitor, & R-warfarin affected only. Plasma binding proteins Albumin, α-glycoprotein Drugs bind, unbound drug is active

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) 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….

20 PHARMACOGENOMICS Tamoxifen and CYP2D6 (cont’d) ENDOXIFEN:
100x receptor affinity 100x potency TWO STEP METABOLIC PATHWAY!!! Endoxifen Knowing this … what do scientists like yourselves ask next?!? Effect of CYP2D6 polymorphisms on Tamoxifen response???

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 At 12 years follow up: ~30% of *4/*4 had an event –VS- 60% of wt/wt. 7Goetz et al. Journal of Clinical Oncology 2005(23)36;

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 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… 8Goetz et al. Journal of Clinical Oncology 2005(23)36;

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 A central source for PK/PD/PGX information….very useful for clinician.

24 a BIG thanks to everyone at
Thank You a BIG thanks to everyone at PK/PD documented or potential intxns. Citation links.

25 QUESTIONS ??? PK/PD documented or potential intxns. Citation links.

26 References American Cancer Society 2006
Baker AF, Dorr RT. Drug interactions with the taxanes: clinical implications. Cancer Treatment Reviews 2001(27); Bjornnson TD, Huang AT, Roth P, Jacob DS, Christenson R. Clinical Pharmacology & Therapeutics (1):25-28 Cozza KL, Armstrong SC, Oesterheld JR. Drug Interaction Principles nd 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 (4); De Jonge ME, Huitema AD, Beijnen JH. Clinical pharmacokinetics of cyclophosphamide. Clinical Pharmacokinetics (11); 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 (36); Hansten PD, Horn JR. Top 100 Drug Interactions 2006 PK/PD documented or potential intxns. Citation links.

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 (10); Lexi-comp. Drug Information Handbook th edition Lodwick R, McConkey B, Brown AM. Life threatening interaction between tamoxifen and warfarin. British Journal of Medicine (6606);1141 Morello KC, Wurz GT, DeGregorio MW. Pharmacokinetics of selective estrogen receptor modulators. Clinical Pharmacokinetics (4); 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 (11); Scripture CD, Figg WD. Drug interactions in cancer therapy. Nature (6); PK/PD documented or potential intxns. Citation links.

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