Transcript Chemotherapy Drug Interactions in the Treatment of

Drug Interactions in Breast
Cancer Chemotherapy
Sunshine S. Gascon
University of Washington
School of Pharmacy
Doctoral Candidate, 2007
October 26, 2006
BREAST CANCER
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Background
Chemotherapy
Drug interactions
Pharmacogenomics
GeneMedRx
BREAST CANCER
Statistics1
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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
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Cyclophosphamide (Cytoxan)
Doxorubicin (Adriamycin)
Paclitaxel (Taxol)
Tamoxifen (Nolvadex)
Trastuzumab (Herceptin)
Side effects
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Nausea/vomiting – antiemetics (Zofran, Reglan, Emend)
Anemia – growth factors (Epogen, Procrit)
Immunocompromised – antibiotics, antifungals
Pain – opiod analgesics (hydrocodone, oxycodone)
CHEMOTHERAPY POLYPHARMACY
Other Medical Conditions
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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
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paclitaxel + doxorubicin = cardiotoxicity
trastuzumab + cyclo/dox = cardiotoxicity
Chemo + Chemo-related
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cyclophosphamide + aprepitant = ↓ chemo efficacy
Chemo + Other
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doxorubicin + digoxin = ↓ digoxin effects
tamoxifen + warfarin = ↑ warfarin effects
CHEMOTHERAPY METABOLISM
Substrates
Cyclophosphamide
Doxorubicin
2B6, 3A4
2C8, 2C9
2C19,2D6
Inducer
Inhibitor
2B6, 3A4,
2C8, 2C9
3A4 (weak)
3A4
2D6, 3A4 (weak)
pGP, 2D6
Paclitaxel
2C8, 3A4
Tamoxifen
2D6, 3A4
pGP
2C8, 3A4 (weak)
pGP, 3A4 (weak)
2C8/9, pGP
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
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Randomized, cross-over study in metastatic breast cancer
patients2
n=10
Dox  Pac
Pac  Dox
Mean Diff
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
Dox Cl
(ml/min)
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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
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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%)
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Increased cardiac dysfunction
3Slamon
et al. NEJM 2001 (344)11; 783-792.
DRUG INTERACTIONS
Chemotherapy + Trastuzumab
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(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
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Mgmt
– Risk:benefit assessment
– Cardiac monitoring (baseline, every three months)
3Slamon
et al. NEJM 2001 (344)11; 783-792.
DRUG INTERACTIONS
Cyclophosphamide + Aprepitant
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Cyclophosphamide4
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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)
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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)
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Mechanism
– Aprepitant inhibits CYP3A4  decreased bioactivation of
cyclophosphamide
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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
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Chemotherapy
– Inhibits growth of rapidly dividing cells
– Affects epithelial cells, hair follicle cells
– Alter GI mucosa lining  alter absorption
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Digoxin
– Effective use in heart failure, arrhythmias
– Strengthens heart contractions
– Therapeutic serum levels 0.8- to 2ng/ml
DRUG INTERACTIONS
Chemotherapy + Digoxin (cont’d)
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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)
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Mechanism – cytotoxic effects of chemotherapy alters GI
absorption of digoxin.
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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
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Tamoxifen
– Selective estrogen receptor modulator (SERM)
– Effect for breast cancer prevention & treatment
– Metabolized primarily by CYP 2D6, 3A4
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Warfarin
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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)
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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
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Mechanism
– Proposed mechanism: plasma protein-binding displacement
warfarin – 99% bound
tamoxifen – 99% bound
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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
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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
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Effect of CYP2D6 polymorphisms on Tamoxifen response???
PHARMACOGENOMICS
Tamoxifen and CYP2D6
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(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
PHARMACOGENOMICS
Tamoxifen and CYP2D6
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(cont’d)
Clinical study8
– Results
HR
(*4/*4:non)
P
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%)
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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.
8Goetz
et al. Journal of Clinical Oncology 2005(23)36; 9312-9318
GeneMedRx
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Drug interactions database
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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
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Achieve goals:
– Improve drug safety and efficacy
– Improve patient response & quality of life
Thank You
a BIG thanks to everyone at
QUESTIONS ???
References
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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
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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.