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

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)
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….

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.

6. NON-CANCER RELATED DRUG
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

8. CHEMOTHERAPY METABOLISM
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.