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

Drug Interactions in Breast Cancer Chemotherapy

Sunshine S. GasconUniversity of Washington

School of PharmacyDoctoral 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 2006http://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-RELATED DRUG

CHEMO DRUG

NON-CANCER RELATED DRUG

EfficacyToxicity

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 Inducer Inhibitor

Cyclophosphamide2B6, 3A4

2C8, 2C92C19,2D6

2B6, 3A4, 2C8, 2C9

3A4 (weak)

Doxorubicin 3A4pGP, 2D6

2D6, 3A4 (weak)

Paclitaxel 2C8, 3A4pGP

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 edHansten & Horn. Top 100 Drug Interactions. 2006 edLexi-comp. Drug Information Handbook. 12th edScripture CD, Figg WD. Nature 2006(6);546-559.

DRUG INTERACTIONSPaclitaxel + Doxorubicin• Randomized, cross-over study in metastatic breast cancer

patients2

n=10 Dox Pac Pac Dox Mean DiffDox 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

2Holmes et al. J Clin Oncol 1996 (14):2713-2721

DRUG INTERACTIONSChemotherapy + 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

3Slamon et al. NEJM 2001 (344)11; 783-792.

DRUG INTERACTIONSChemotherapy + 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)

3Slamon et al. NEJM 2001 (344)11; 783-792.

DRUG INTERACTIONSCyclophosphamide + 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 INTERACTIONSCyclophosphamide + 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 INTERACTIONSChemotherapy + 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 INTERACTIONSChemotherapy + 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 INTERACTIONSTamoxifen + 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 INTERACTIONSTamoxifen + 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.

PHARMACOGENOMICSTamoxifen 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)

PHARMACOGENOMICSTamoxifen and CYP2D6 (cont’d)

ENDOXIFEN:•100x receptor affinity•100x potency

• Effect of CYP2D6 polymorphisms on Tamoxifen response???

PHARMACOGENOMICSTamoxifen 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

7Goetz et al. Journal of Clinical Oncology 2005(23)36; 9312-9318

PHARMACOGENOMICSTamoxifen 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

8Goetz et al. Journal of Clinical Oncology 2005(23)36; 9312-9318

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.