Drug Interactions in Breast Cancer Chemotherapy[1]

Drug Interactions in Breast Cancer Chemotherapy Sunshine S. Gascon University of Washington School of Pharmacy Doctoral Candidate, 2007 October 26, 2006 BREAST CANCER • • • • • Background Chemotherapy Drug interactions Pharmacogenomics GeneMedRx 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 1American Cancer Society 2006 http://www.cancer.org/docroot/STT/content/STT_1x_Cancer_Facts__Figures_2006.asp 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) 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. DRUG INTERACTIONS CHEMO DRUG Efficacy Toxicity CHEMO-RELATED DRUG NON-CANCER RELATED DRUG 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 CHEMOTHERAPY METABOLISM Substrates Cyclophosphamide Doxorubicin Inducer 2B6, 3A4, 2C8, 2C9 Inhibitor 3A4 (weak) 2B6, 3A4 2C8, 2C9 2C19,2D6 3A4 pGP, 2D6 2D6, 3A4 (weak) Paclitaxel Tamoxifen 2C8, 3A4 pGP 2C8, 3A4 (weak) 2D6, 3A4 2C8/9, pGP pGP, 3A4 (weak) Trastuzumab 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. n/a DRUG INTERACTIONS Paclitaxel + Doxorubicin • Randomized, cross-over study in metastatic breast cancer patients2 n=10 Dox Cl (ml/min) Dox Cmax (ng/ml) Granulocyte counts Stomatitis (# patients) Dox  Pac 51 ± 16 26 ± 5 Pac  Dox 34 ± 10 45 ± 8 Mean Diff 32% 70% 1.3/ul 1 0.2/ul 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 2Holmes et al. J Clin Oncol 1996 (14):2713-2721 DRUG INTERACTIONS Chemotherapy + Trastuzumab • Randomized, controlled, phase III clinical trial in metastatic breast cancer patients3 Cyclo/Dox (n=135) Response (%) Cardiotox (%) 58 8 Cyclo/Dox + Trastuzumab (n=143) 80 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 3Slamon et al. NEJM 2001 (344)11; 783-792. DRUG INTERACTIONS Chemotherapy + Trastuzumab • Mechanism – Proposed: Her2 expression in cardiac tissues – Prevailing: Cyclo/Dox cause cardiac tissue damage, Trastuzumab impairs cellular repair time – Currently unknown PD interaction (cont’d) • Mgmt – Risk:benefit assessment – Cardiac monitoring (baseline, every three months) 3Slamon et al. NEJM 2001 (344)11; 783-792. 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) 4de Jonge et al. Clinical Pharmacokinetics. 2005(44)11; 1135-1164 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) 5de Jonge et al. Cancer Chemotherapy & Pharmacology 2005. 56(4):370-378 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 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 6Bjornnson et al. Clin Pharmacol Ther. 1986 Jan;39(1):25-8 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 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 DRUG INTERACTIONS Most drug interactions are manageable (monitoring, dose reduction, dose timing), indicating the importance of a central source for drug interaction information. 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) PHARMACOGENOMICS Tamoxifen and CYP2D6 (cont’d) ENDOXIFEN: • 100x receptor affinity • 100x potency • Effect of CYP2D6 polymorphisms on Tamoxifen response??? PHARMACOGENOMICS Tamoxifen and CYP2D6 • 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 (cont’d) – Endpoints • Disease-free time • Overall survival • Hot flashes 7Goetz et al. Journal of Clinical Oncology 2005(23)36; 9312-9318 PHARMACOGENOMICS Tamoxifen and CYP2D6 • Clinical study8 – Results HR (*4/*4:non) Disease-free Overall survival 1.86 1.12 P 0.089 0.780 (cont’d) • 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. et al. Journal of Clinical Oncology 2005(23)36; 9312-9318 8Goetz 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 Thank You a BIG thanks to everyone at QUESTIONS ??? 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 • • • 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. •