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

2
BREAST CANCER

• Background
• Chemotherapy
• Drug interactions
• Pharmacogenomics
• GeneMedRx

3
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.or
g/docroot/STT/content/STT_1x_Cancer_Facts__Figures
_2006.asp
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.
6
DRUG INTERACTIONS
CHEMO DRUG
Efficacy Toxicity
CHEMO-RELATED DRUG
NON-CANCER RELATED DRUG
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
Substrates Inducer Inhibitor
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)
Trastuzumab n/a n/a 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.
12th ed Scripture CD, Figg WD. Nature
2006(6)546-559.
9
DRUG INTERACTIONS

• Paclitaxel Doxorubicin
• Randomized, cross-over study in metastatic breast
  cancer patients2

n10 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

2Holmes et al. J Clin Oncol 1996 (14)2713-2721
10
DRUG INTERACTIONS

• Chemotherapy Trastuzumab
• Randomized, controlled, phase III clinical trial
  in metastatic breast cancer patients3

Cyclo/Dox (n135) Cyclo/Dox Trastuzumab (n143)
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.
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
• Riskbenefit assessment
• Cardiac monitoring (baseline, every three months)

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

4de Jonge et al. Clinical Pharmacokinetics.
2005(44)11 1135-1164
13
DRUG INTERACTIONS

• Cyclophosphamide Aprepitant (contd)
• Clinical trial5
• Co-administration (n6) compared to reference
  group (n49)
• 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
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 trial6
• Patients (n6) receiving digoxin before after
  chemotherapy.
• Results Digoxin AUC decreased by nearly 55
• (31.8 vs 17.4 nghr/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
Jan39(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. 2003 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 2003.
42(4)361-372
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 study7
• Breast cancer women (n223) 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
22
PHARMACOGENOMICS

• Tamoxifen and CYP2D6 (contd)
• Clinical study8
• Results
• CYP 2D64/4 shown to have shorter time to
  disease recurrence
• CYP 2D64/4 genotypes did not experience hot
  flashes
• (non-4/4 had gt20)
• 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 (4/4non) 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
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
25
QUESTIONS ???
26
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

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 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.