Presentation on theme: "Drug Interactions in Breast Cancer Chemotherapy"— Presentation transcript:
1Drug Interactions in Breast Cancer Chemotherapy Sunshine S. GasconUniversity of WashingtonSchool of PharmacyDoctoral Candidate, 2007October 26, 2006
2BREAST CANCER Background Chemotherapy Drug interactions PharmacogenomicsGeneMedRxBackground – statistics, treatment optionsChemotherapy – polypharmacy & various drug used in breast cancer treatmentDrug interactions – specific examplesPharmacogenomics – pipeline genotyping (2D6 & tamoxifen)GeneMedRx – the role of GeneMedRx
3BREAST CANCER Statistics1 Treatment options Most prevalent type in women (31%)Median age – 40yoIncidence – 210,000 new casesMortality – 71,000 women (33%)Treatment optionsSurgeryRadiation therapyChemotherapyPrevalence 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 deathsTreatment options: surgery (lumpectomy, masectomy, double masectomy), radiation, chemotherapy – chemical therapy!1American Cancer Society 2006
4CHEMOTHERAPY POLYPHARMACY Chemotherapy AgentsCyclophosphamide (Cytoxan)Doxorubicin (Adriamycin)Paclitaxel (Taxol)Tamoxifen (Nolvadex)Trastuzumab (Herceptin)Side effectsNausea/vomiting – antiemetics (Zofran, Reglan, Emend)Anemia – growth factors (Epogen, Procrit)Immunocompromised – antibiotics, antifungalsPain – opiod analgesics (hydrocodone, oxycodone)Chemotherapy agentsSingle/comboStage of diseaseDifferent targets of cell cycleEFFECTIVE…but SEs!!!As you can see…. Many chemo drugs… BUT…more conditions….
5CHEMOTHERAPY POLYPHARMACY Other Medical ConditionsAge related – birth control, menopause, osteoporosisArthritis – NSAIDS, etanercept (Enbrel)Cardiovascular – hypertension, arrhythmiasAnticoagulants – warfarinEndocrine – diabetes, hyperlipidemiaEpilepsy – phenytoin, carbamazepineHIV/AIDS – NRTIs, PIsSSRIsChemotherapy regimens can be numerous,allowing for many potential adverse drug interactions.
6NON-CANCER RELATED DRUG DRUG INTERACTIONSCHEMO DRUGEfficacyToxicityVariations of drug interactions (chemo + chemo, chemo + other…) = can alter efficacy & toxicity profile.CHEMO-RELATED DRUGNON-CANCER RELATED DRUG
8CHEMOTHERAPY METABOLISM SubstratesInducerInhibitorCyclophosphamide2B6, 3A42C8, 2C92C19,2D62B6, 3A4,3A4 (weak)Doxorubicin3A4pGP, 2D62D6, 3A4 (weak)Paclitaxel2C8, 3A4pGP2C8, 3A4 (weak)Tamoxifen2D6, 3A4 2C8/9, pGPpGP, 3A4 (weak)Trastuzumabn/aSeveral resourcesWeak inducer/inhibitorsCyclo exception – moderate autoinducerSubstrates – 3A4, pGP (efflux transporter – excrete drugs!)Trastuzumab – monoclonal antibody (degraded in tissues)Bold = major pathwayCozza et al. Drug Interaction Principles edHansten & Horn. Top 100 Drug Interactions edLexi-comp. Drug Information Handbook. 12th edScripture CD, Figg WD. Nature 2006(6);
9DRUG INTERACTIONS Paclitaxel + Doxorubicin Randomized, cross-over study in metastatic breast cancer patients2n=10Dox PacPac DoxMean DiffDox Cl (ml/min)51 ± 1634 ± 1032%Dox Cmax (ng/ml)26 ± 545 ± 870%Granulocyte counts1.3/ul0.2/ulStomatitis(# patients)17Chemotherapy interactionCommon chemo combo = Paclitaxel + DoxorubicinResearchers looked at affect on each otherDox (48hrs) Pac (24hrs), Pac Dox (Cl reduced ~30%)Increased SE granulocyte, stomatitis (mucositis)Paclitaxel given before doxorubicin decreases dox ClLeads to increased side effects (SEs)Mechanism – PK interaction (3A4, pGP competition)Mgmt – doxorubicin 24hrs prior to paclitaxel2Holmes et al. J Clin Oncol 1996 (14):
10Cyclo/Dox + Trastuzumab DRUG INTERACTIONSChemotherapy + TrastuzumabRandomized, controlled, phase III clinical trial in metastatic breast cancer patients3Cyclo/Dox(n=135)Cyclo/Dox + Trastuzumab(n=143)Response (%)5880Cardiotox (%)827Trastuzumab increased responseLonger 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 dysfunctionFairly large studyResponse:Time to disease progression (7.4 vs 4.6 months)Longer survival (25.1 vs 20.3 months) – f/u for 30months20% reduction in death riskBUT – increased cardiac dysfunction (x3 fold!!!)Generally responsive to treatment3Slamon et al. NEJM 2001 (344)11;
11DRUG INTERACTIONS Chemotherapy + Trastuzumab (cont’d) Mechanism Mgmt Proposed: Her2 expression in cardiac tissuesPrevailing: Cyclo/Dox cause cardiac tissue damage,Trastuzumab impairs cellular repair timeCurrently unknown PD interactionMgmtRisk:benefit assessmentCardiac monitoring (baseline, every three months)DDI MechanismProposed mechanism – Her2/Neu receptors on myocardium (none!), Herceptin alone = no cardiac toxPrevailing theory - maybe Herceptin decreases cardiac cell repair time induced by Cy/Dox.Mechanism is currently unknown – BUT with GeneMedRx alert – MD can better manage.Mgmtrisk:benefit assessment (age, history of cardiac dysfunction)Cardiac monitoring (EKG, ejection fraction)3Slamon et al. NEJM 2001 (344)11;
12DRUG INTERACTIONS Cyclophosphamide + Aprepitant Cyclophosphamide4 Effective anti-tumor agentProdrug bioactivation (via CYP3A4 to 4-OH-cyclophosphamide)AutoinducerHigh emetogenic potentialAprepitant (Emend)Effective for acute and delayed emesisDosing 1hr prior to several days post-chemoCYP3A4 substrate, inhibitor (moderate)Emetogenic potential = 90% will experience N/VAprepitant…INHIBITOR!!!So.. Clinical trial looking at effect of aprepitant on cyclophos4de Jonge et al. Clinical Pharmacokinetics. 2005(44)11;
13DRUG INTERACTIONS Cyclophosphamide + Aprepitant (cont’d) Clinical trial5Co-administration (n=6) compared to reference group (n=49)Measured cyclophosphamide & metabolite levelsReduction in 4-OH-cyclophosphamide (5%)Reduction in enzyme induction (7%)Less nausea/vomiting with aprepitant (0.5 vs 4.8 days)MechanismAprepitant inhibits CYP3A4 decreased bioactivation of cyclophosphamideMgmtMonitor for unexpected lack of anti-tumor responseModify chemo regimen as necessaryCaution with use of other 3A4 inhibitors (antibiotics, antifungals)SMALL STUDYLooked at Aprepitant effect Cyclo metabolismAprepitant (one day prior, x4days, +3days post chemo) = 8days totalWhile 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):
14DRUG INTERACTIONS Chemotherapy + Digoxin Chemotherapy Digoxin Inhibits growth of rapidly dividing cellsAffects epithelial cells, hair follicle cellsAlter GI mucosa lining alter absorptionDigoxinEffective use in heart failure, arrhythmiasStrengthens heart contractionsTherapeutic serum levels 0.8- to 2ng/ml
15DRUG 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.MgmtMonitor for unexpected lack of response to digoxinMonitor digoxin levelsAdjust digoxin dose accordinglyNo adverse clinical effect noted6Bjornnson et al. Clin Pharmacol Ther Jan;39(1):25-8
16DRUG INTERACTIONS Tamoxifen + Warfarin Tamoxifen Warfarin Selective estrogen receptor modulator (SERM)Effect for breast cancer prevention & treatmentMetabolized primarily by CYP 2D6, 3A4WarfarinOral anticoagulantEffective for stroke, DVT/PE prophylaxisNarrow therapeutic window (usual INR 2-3)Metabolized primarily by CYP 2C9, 3A4Currently no clinical trialsCozza et al. Drug Interaction Principles ed
17DRUG INTERACTIONS Tamoxifen + Warfarin (cont’d) Clinical evidence Several case reports65yo woman stabilized on warfarin (x11yrs) increased PT time(required 40% dose reduction)Woman stabilized on 25mg/d warfarin subdural hematomaMechanismProposed mechanism: plasma protein-binding displacementwarfarin – 99% boundtamoxifen – 99% boundManagementClose PT/INR monitoringAdjust warfarin dose accordinglyMechanism: tamoxifen is only a weak 3A4 inhibitor, & R-warfarin affected only.Plasma binding proteinsAlbumin, α-glycoproteinDrugs bind, unbound drug is activeMorello et al. Clinical Pharmacokinetics (4);
18DRUG INTERACTIONSMost 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 proteinsAlbumin, α-glycoproteinDrugs bind, unbound drug is active
19PHARMACOGENOMICS Tamoxifen and CYP2D6 Tamoxifen SERM (selective estrogen receptor modulator)Estrogen receptor (ER) antagonist in breast inhibits cell growthEffective use in ER (+) tumorsMetabolism to active metabolite via CYP2D6SEs: menopausal symptoms (night sweats, hot flashes)Adjuvant therapy – postoperative and/or with chemoPreventative therapy – only in high risk, due to risk of endometrial cancer, DVT/PE, stroke.ER agonist/antagonistSEs = hot flashes, night sweatsMETABOLISM….
20PHARMACOGENOMICS Tamoxifen and CYP2D6 (cont’d) ENDOXIFEN: 100x receptor affinity100x potencyTWO STEP METABOLIC PATHWAY!!!EndoxifenKnowing this … what do scientists like yourselves ask next?!?Effect of CYP2D6 polymorphisms on Tamoxifen response???
21PHARMACOGENOMICS Tamoxifen and CYP2D6 (cont’d) Clinical study7 Breast cancer women (n=223) received tamoxifen (x5yrs) post-tumor removalGenotyped for CYP2D6WT/WT (72.1%) – Extensive MetabolizerWT/*4 (21.1%) – Intermediate metabolizer*4/*4 ( 6.8 %) – Poor metabolizerEndpointsDisease-free timeOverall survivalHot flashesAt 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;
22PHARMACOGENOMICS Tamoxifen and CYP2D6 (cont’d) Clinical study8 ResultsCYP 2D6*4/*4 shown to have shorter time to disease recurrenceCYP 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)PDisease-free1.860.089Overall survival1.120.780PM > 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;
23GeneMedRx Drug interactions database PharmacokineticPharmacodynamicPharmacogenomicClincial evidence (trials, case-reports)Potential drug interactionsKnowledge of drug interactions allows practitioners to:Optimize patient’s medication managementMonitor efficacy and toxicityModify dose, administration, drug selectionAchieve goals:Improve drug safety and efficacyImprove patient response & quality of lifeA central source for PK/PD/PGX information….very useful for clinician.
24a BIG thanks to everyone at Thank Youa BIG thanks to everyone atPK/PD documented or potential intxns. Citation links.
25QUESTIONS ???PK/PD documented or potential intxns. Citation links.
26References 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):25-28Cozza KL, Armstrong SC, Oesterheld JR. Drug Interaction Principles nd editionDe 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 2006PK/PD documented or potential intxns. Citation links.
27ReferencesHolmes 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 editionLodwick R, McConkey B, Brown AM. Life threatening interaction between tamoxifen and warfarin. British Journal of Medicine (6606);1141Morello 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.