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
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

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 NON-CANCER RELATED

DRUG 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 Inducer Inhibitor

2B6, 3A4 2B6, 3A4,
Cyclophosphamide 2C8, 2C9 2C8, 2C9
3A4 (weak)
2C19,2D6

Doxorubicin 3A4 2D6, 3A4 (weak)

pGP, 2D6

Paclitaxel 2C8, 3A4 2C8, 3A4 (weak)

pGP

Tamoxifen 2D6, 3A4 pGP, 3A4 (weak)

2C8/9, pGP

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. 12 th ed
Scripture CD, Figg WD. Nature 2006(6);546-559.
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

DRUG INTERACTIONS
Chemotherapy + Trastuzumab
• Randomized, controlled, phase III clinical trial in metastatic
breast cancer patients3
Cyclo/Dox +
Cyclo/Dox
Trastuzumab
(n=135)
(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.

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.

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
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
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

6
Bjornnson 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 (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
PHARMACOGENOMICS
Tamoxifen and CYP2D6 (cont’d)
• Clinical study8
– Results

HR
P
(*4/*4:non)
Disease-free 1.86 0.089
Overall survival 1.12 0.780

• 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.

8
Goetz 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. 2 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 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.