Presentation is loading. Please wait.

Presentation is loading. Please wait.

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

Similar presentations

Presentation on theme: "Drug Interactions in Breast Cancer Chemotherapy Sunshine S. Gascon University of Washington School of Pharmacy Doctoral Candidate, 2007 October 26, 2006."— Presentation transcript:

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

3 BREAST CANCER Statistics 1 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

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 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.


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 CHEMOTHERAPY METABOLISM SubstratesInducerInhibitor 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) Trastuzumabn/a Bold = major pathway Cozza et al. Drug Interaction Principles ed Hansten & Horn. Top 100 Drug Interactions ed Lexi-comp. Drug Information Handbook. 12 th ed Scripture CD, Figg WD. Nature 2006(6);

9 DRUG INTERACTIONS Paclitaxel + Doxorubicin Randomized, cross-over study in metastatic breast cancer patients 2 n=10Dox PacPac DoxMean Diff Dox Cl (ml/min) 51 ± 1634 ± 1032% Dox Cmax (ng/ml) 26 ± 545 ± 870% Granulocyte counts 1.3/ul0.2/ul Stomatitis (# patients) 17 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):

10 DRUG INTERACTIONS Chemotherapy + Trastuzumab Randomized, controlled, phase III clinical trial in metastatic breast cancer patients 3 Cyclo/Dox (n=135) Cyclo/Dox + Trastuzumab (n=143) Response (%)5880 Cardiotox (%)827 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;

11 DRUG INTERACTIONS Chemotherapy + Trastuzumab (contd) 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;

12 DRUG INTERACTIONS Cyclophosphamide + Aprepitant Cyclophosphamide 4 –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;

13 DRUG INTERACTIONS Cyclophosphamide + Aprepitant (contd) Clinical trial 5 –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 (4):

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 DRUG INTERACTIONS Chemotherapy + Digoxin (contd) Clinical trial 6 –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 Jan;39(1):25-8

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 ed

17 DRUG INTERACTIONS Tamoxifen + Warfarin (contd) 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 (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.

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 PHARMACOGENOMICS Tamoxifen and CYP2D6 (contd) ENDOXIFEN: 100x receptor affinity 100x potency Effect of CYP2D6 polymorphisms on Tamoxifen response???

21 PHARMACOGENOMICS Tamoxifen and CYP2D6 (contd) Clinical study 7 –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;

22 PHARMACOGENOMICS Tamoxifen and CYP2D6 (contd) Clinical study 8 –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 Overall survival Goetz 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 patients 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 Thank You a BIG thanks to everyone at


26 References American Cancer Society 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

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);

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

Similar presentations

Ads by Google