Drug Interactions in Oncology: Which Interactions Really Matter?

Drug Interactions in Oncology: Which Interactions Really Matter?

Suphat Subongkot, PharmD, BCPS, BCOP

Assistant ProfessorPharmacy Practice DivisionKhon Kaen UniversityKhon Kaen, Thailand

Suphat Subongkot, PharmD, BCPS, BCOP

Assistant ProfessorPharmacy Practice DivisionKhon Kaen UniversityKhon Kaen, Thailand

Learning ObjectivesLearning Objectives

Describe the principles of drug interactions

List common drug interactions in oncology Explain the impact of drug interactions in

cancer care

Describe the principles of drug Describe the principles of drug interactionsinteractions

List common drug interactions in oncologyList common drug interactions in oncology Explain the impact of drug interactions in Explain the impact of drug interactions in

cancer carecancer care

DisclosureDisclosure

Suphat Subongkot, PharmD, BCPS, BCOP has no real or apparent conflicts of interest to report

Suphat Subongkot, PharmD, BCPS, BCOP has no real or apparent conflicts of interest to report

CaseCase

CC: 42-year-old woman presents to the hospital with a 2-cm lump on her left breast

HPI: Diagnosed with stage II breast cancer ~ 4 weeks ago Admitted to receive adriamycin,

cyclophosphamide, paclitaxel, and trastuzumab PMH: COPD x 5 years, GERD x 2 years FH:

No family history of cancer Smoked 2 pack per day x 15 years (quit ~ 2 weeks

ago)

CC: 42-year-old woman presents to the hospital with a 2-cm lump on her left breast

HPI: Diagnosed with stage II breast cancer ~ 4 weeks ago Admitted to receive adriamycin,

cyclophosphamide, paclitaxel, and trastuzumab PMH: COPD x 5 years, GERD x 2 years FH:

No family history of cancer Smoked 2 pack per day x 15 years (quit ~ 2 weeks

ago)

Case (cont.)Case (cont.)

Allergy: NKDAHome medications:

Albuterol + ipratropium 2 puffs qid Omeprazole 30 mg bid

Medication on admission: Adriamycin + paclitaxel + trastuzumab Tamoxifen Omeprazole Ondasetron + aprepitant + dexamethasone Sertraline

Allergy: NKDAAllergy: NKDAHome medications:Home medications:

AlbuterolAlbuterol + + ipratropiumipratropium 2 puffs 2 puffs qidqid OmeprazoleOmeprazole 30 mg bid 30 mg bid

Medication on admission:Medication on admission:

AdriamycinAdriamycin + + paclitaxelpaclitaxel + + trastuzumabtrastuzumab TamoxifenTamoxifen OmeprazoleOmeprazole OndasetronOndasetron + + aprepitantaprepitant + + dexamethasonedexamethasone SertralineSertraline

What Could Be a Potential DRP?What Could Be a Potential DRP?

DRP = Drug-related problem

Drug InteractionsDrug Interactions

CHEMO-RELATED DRUG

CHEMO DRUG

NON-CANCER RELATED DRUG

EfficacyToxicity

IntroductionIntroduction

Patients with cancer are at considerable risk of drug interactions due to A large number of drugs during their

treatment

Patients with cancer are at considerable Patients with cancer are at considerable risk of drug interactions due torisk of drug interactions due to A large number of drugs during their A large number of drugs during their

treatmenttreatment

Ernst E, Cassileth BR. Cancer. 1998;83:777-82.

PolypharmacyPolypharmacy

Chemotherapy Agents Cyclophosphamide (Cytoxan) Doxorubicin (Adriamycin) Paclitaxel (Taxol) Tamoxifen (Nolvadex) Trastuzumab (Herceptin)

Supportive Care Nausea/vomiting antiemetics (5-HT3 antagonist, dopamine

receptor antagonist, NK-1 receptor antagonist) Anemia erythopoetin stimulating agents (ESAs) Immunocompromised antibiotics, antifungals Pain opioid analgesics (hydrocodone, oxycodone)

Introduction (cont)Introduction (cont)

Complementary Alternative Medicines 51.6% of patients with cancer were taking

complementary alternative medicines 12.2% were subsequently issued a health

warning

Complementary Alternative MedicinesComplementary Alternative Medicines 51.6% of patients with cancer were taking 51.6% of patients with cancer were taking

complementary alternative medicinescomplementary alternative medicines 12.2% were subsequently issued a health 12.2% were subsequently issued a health

warning warning

Werneke U, et al. Br J Cancer. 2004;90:408-13.

Introduction (cont)Introduction (cont)

Aging Population Approximately 60% of patients with cancer are

aged 65 years or over

Aging PopulationAging Population Approximately 60% of patients with cancer are Approximately 60% of patients with cancer are

aged 65 years or over aged 65 years or over

Yancik R, Ries LAG. Hematol Oncol Clin North Am. 2000;14 :17-23 ; Yancik R, et al. J Clin Oncol. 2001;19 1147-54.

Introduction (cont)Introduction (cont)

Aging Population 78% of patients over 65 years of age are

taking prescription medications 39% regularly take five or more drugs

Aging PopulationAging Population 78% of patients over 65 years of age are 78% of patients over 65 years of age are

taking prescription medicationstaking prescription medications 39% regularly take five or more drugs 39% regularly take five or more drugs

Jrgensen T, et al. Ann Pharmacother. 2001;35:1004-9.

PolypharmacyPolypharmacy

Other Medical Conditions Age related: birth control, menopause, osteoporosis Arthritis: NSAIDS, TNF alpha inhibitors Cardiovascular: hypertension, arrhythmias Anticoagulants: warfarin Endocrine: diabetes, hyperlipidemia Epilepsy: phenytoin, carbamazepine HIV/AIDS: NRTIs, PIs SSRIs

NRTIs = Non-nucleotide reverse transcriptase inhibitors; PI=Protease Inhibitors; SSRI=Selective Serotonin Reuptake Inhibitors

Incidence Related to Concomitant Drugs Incidence Related to Concomitant Drugs

Number of Drugs Estimated (%) Actual (%)

2

3

4

5

6

7

8

5.6

16.8

33.6

56

84

100

100

5.6

15.8

34.3

46.7

72

66

100

Karas S, Jr. Ann Emerg Med. 1981;10: 627-30.

Why Is it Important?Why Is it Important?

Physiological changes due to drug interactions may be confused with Symptoms and signs of cancer Combined illnesses Adverse effects of antineoplastic agents

Physiological changes due to drug Physiological changes due to drug interactions may be confused with interactions may be confused with Symptoms and signs of cancer Symptoms and signs of cancer Combined illnessesCombined illnesses Adverse effects of Adverse effects of antineoplasticantineoplastic agents agents

Frequency and SeverityFrequency and Severity

Variable No. %No. of patients participated

No. of patients with potential DI

No. of potential DI indentified

Severity of drug interactions

Major

Moderate

Minor

405

109

276

25

84

100

100

27

100

9

77

14

Rachel P, et al. J Natl Cancer Inst. 2007;99:592-600. DI = drug interaction

Mechanism of Identified Potential Drug Interactions Mechanism of Identified Potential Drug Interactions

Variable (N = 405) No. %No. of potential drug interactions

Mechanism of identified potential DI

Pharmacokinetic

Pharmacodynamic

Unknown

276

151

70

55

100

55

25

20

Rachel P, et al. J Natl Cancer Inst. 2007;99:592-600.

Types of Drug InteractionsTypes of Drug Interactions

Pharmaceutical interactions Pharmacokinetic interactions Pharmacodynamic interactions

Pharmaceutical interactionsPharmaceutical interactions Pharmacokinetic interactionsPharmacokinetic interactions PharmacodynamicPharmacodynamic interactionsinteractions

Beijnen JH, Schellens JHM. Lancet Oncology. 2004;5:489-96.

Pharmaceutical InteractionsPharmaceutical Interactions

Drug 1 Drug 2 Outcomes

Mesna CisplatinA covalent

mesna-platinum adduct

Mitomycin D5W (pH 4-5) Inactive mitosenes

Taxanes

EtoposideSome IV fluids Precipitation

Incompatibility either physically or chemicallyIncompatibility either physically or chemically

Verschraagen M. Cancer Chemother Pharmacol. 2003;51:499-504; Beijnen JH. J Pharm Biomed Anal. 1986;4:275-95.

Pharmacokinetic InteractionsPharmacokinetic Interactions

AbsorptionDistributionMetabolismExcretion

Scripture CD et al. Nat Rev Cancer 2006; 6(7):546-558

Pharmacokinetic Interactions (Absorption) Pharmacokinetic Interactions (Absorption)

Effect Example

Altered absorption Allopurinol and 6-MP

Areas for potential drug interactionsAreas for potential drug interactions

6-MP = 6-Mercaptopurine

Lennard L. Eur J Clin Pharmacol 1992; 43:329-339; Poplack DG, et al. Cancer 1986; 58: 437-480

6-MP and Allopurinol6-MP and Allopurinol

With allopurinol

Without allopurinol

Allopurinol 100 mg tid x 2 day

6-MP 75 mg PO

Adapted from Poplack DG. Cancer. 1986;58:473-80.

Effect of Food on Oral Anticancer Agents Effect of Food on Oral Anticancer Agents

Drug Effect of Food PK Parameters

Busulfan

5-FU

Methotrexate

Topotecan

Delayed absorption

(effect on rate)

Change in Cmax and Tmax

Schuler U, et al. BMT. 1994;14:759-65; Janish, et al. Proc ASCO 1998 (abst 862); Pinkerton CR, et al. Lancet. 1980;2:944-46; Herben VM, et al. Br J Cancer. 1999;80:1380-86 .

Cmax = Maximum Plasma Concentration

Tmax = Time to Maximum Plasma Concentration

Effect of Food on Oral Anticancer Agents Effect of Food on Oral Anticancer Agents

Drug Effect of Food PK ParametersAltretamine

Capecitabine

Chlorambucil

Estramustine

Gefitinib

Melphalan

Thioguanine

Delayed absorption

(effect on extent)

Change in AUC and Cmax

Scripture CD, Figg WD. Nat Rev Cancer. 2006;6:546-88.

AUC= Area under the plasma (serum, or blood) concentration versus time curveCmax = Maximum Plasma Concentration

Effect of Food on Oral Anticancer Agents Effect of Food on Oral Anticancer Agents

Drug Effect of Food PK Parameters

Erlotinib

Tretinoin

Increased absorption (effect on extent and/or

rate)

Increase in AUC and usually Cmax

and/or Tmax

Scripture CD, Figg WD. Nat Rev Cancer. 2006;6:546-88.

AUC= Area under the plasma (serum, or blood) concentration versus time curveCmax = Maximum Plasma Concentration Tmax = Time to Maximum Plasma Concentration

Effect of Food on Oral Anticancer Agents Effect of Food on Oral Anticancer Agents

Drug Effect of Food PK ParametersEtoposide

Imatinib

Mercaptopurine

Temozolomide

Unaffected absorption

(No effect on rate

or extent)

No significant change in AUC and

Cmax

Scripture CD, Figg WD. Nat Rev Cancer. 2006;6:546-88.

AUC= Area under the plasma (serum, or blood) concentration versus time curveCmax = Maximum Plasma Concentration

Pharmacokinetic Interactions (Distribution) Pharmacokinetic Interactions (Distribution)

Effect Example

Highly protein-bound Paclitaxel and etoposide

Areas for potential drug interactionsAreas for potential drug interactions

Benet LZ, Hoener BA. Clin Pharmacol Ther. 2002;71:115-21.

Pharmacokinetic Interactions (Metabolism) Pharmacokinetic Interactions (Metabolism)

Effect Example

Increased metabolism Anticonvulsants and irinotecan

Areas for potential drug interactionsAreas for potential drug interactions

McLoed H. Br J Clin Pharmacol. 1998;45:539-44.

Pharmacokinetic Interactions (Metabolism) Pharmacokinetic Interactions (Metabolism)

Hepatic MetabolismHepatic Metabolism Example Drugs

CYP 3A4 Cyclophosphamide

Etoposide

Paclitaxel

Vinka alkaloids

Imatinib

Dihydropyrimidine dehydrogenase 5-FU

Thiopurine methyltransferase 6-MP

CYP = Cytochrome P450, a member of the cytochrome P450 mixed-function oxidase system

Irinotecan and CYP 3A4 InducerIrinotecan and CYP 3A4 Inducer

Source: Nat Rev Cancer Nature Publishing Group

CES = Carboxylesterase

CYP = Cytochrome P450

UGT = UDP-glucuronosyltransferase,

CPT-11= IrinotecanSN-38 = Irinotecan activemetabolite

Herbal Supplements: SJWHerbal Supplements: SJW

Meijerman I, et al. Oncologist. 2006;11:742-52.

SJW = St. Johns wort

HAARTHAART

Effect ExampleCYP system

Substrates

Inhibitors

Inducers

ABCB1 (ATP-binding cassette)

Protease Inhibitors (PIs)

NNRTIs

Areas for potential drug interactionsAreas for potential drug interactions

Huang L, et al. Drug Metab Dispos. 2001;29:754-60.HAART = Highly active antiretroviral therapy; NNRTIs = Non-nucleotide reverse transcriptase inhibitors

ImatinibImatinib

Drug Effect Mechanism Mgmt

Opiates Increase sedation (common)

CYP2D6 inhibition

Decrease dose

Statins Increased rhabdomyolysis (rare)

CYP3A4 inhibition

Monitor signs of weakness, lethargy

Warfarin Increased bleeding CYP3A4 inhibition

Monitor INR

Leveque D, et al. In Vivo. 2005;19:77-84; Frye RF, et al. Clin Pharmacol Ther. 2004;76:323-29; Dutreix C, et al. Cancer Chemother Pharmacol. 2004;54:290-94.

Interpatient VariabilityInterpatient Variability

Evidence of an inherited basis for drug response dates back in the literature to the 1950s Succinylcholine: 1 in 3000 patients developed

prolonged muscle relaxation

Monogenic Phenotype to genotype approach

Evidence of an inherited basis for drug Evidence of an inherited basis for drug response dates back in the literature to the response dates back in the literature to the 1950s1950s SuccinylcholineSuccinylcholine: 1 in 3000 patients developed : 1 in 3000 patients developed

prolonged muscle relaxationprolonged muscle relaxation

MonogenicMonogenic Phenotype to genotype approachPhenotype to genotype approach

Kalow W, Grant DM. Pharmacogenetics. In Scriver CR, Beaudet AL, Sly WS, et al. eds. The Metabolic & Melecular Basis of Inherited Disease. New York, St.Louise, San Franscisco, Aukland, Bogota: McGraw Hill; 2001:225-55.

Drug Metabolizing EnzymesDrug Metabolizing Enzymes

Kalow W, Grant DM. Pharmacogenetics. In Scriver CR, Beaudet AL, Sly WS, et al. eds. The Metabolic & Melecular Basis of Inherited Disease. New York, St.Louise, San Franscisco, Aukland, Bogota: McGraw Hill; 2001:225-55.

Examples of Drug Metabolism Pharmacogenomics, Phase 1* Examples of Drug Metabolism Pharmacogenomics, Phase 1*

Drug-Metabolizing Enzyme

Frequency of Variant Poor-Metabolism

PhenotypeRepresentative Drugs

Metabolized Effect of Polymorphism

Cytochrome P-450 2D6 (CYP2D6)

6.7% in Sweden1% in China

DebrisoquinSparteineNortriptylineCodeine

Enhanced drug effectEnhanced drug effectEnhanced drug effectDecreased drug effect

Cytochrome P-450 2C9(CYP2C9)

Approximately 3% in England (those homozygous for the *2 and *3 alleles)

WarfarinPhenytoin

Enhanced drug effect

Cytochrome P-450 2C19(CYP2C19)

2.7% among white Americans; 3.3% in Sweden; 14.6% in China; 18% in Japan

Omeprazole Enhanced drug effect

Dihydropyrimidine dehydrogenase

Approximately 1% of population is heterozygous

Fluorouracil Enhanced drug effect

Butyrylcholinesterase (pseudocholinesterase)

Approximately 1 in 3500 Europeans

Succinylcholine Enhanced drug effect

*Examples of genetically polymorphic phase 1 enzymes are listed that catalyze drug metabolism, including selected examples of Drugs that have clinically relevant variations in their effects. Weinshilboum R. N Engl J Med. 2003;348:529-37.

Ultimate FateUltimate Fate

Inactive Inactive metabolitemetabolite

Abnormal Abnormal RNARNA synthesissynthesis

Inhibit DNA Inhibit DNA synthesis synthesis through through inhibition of TSinhibition of TS

55--FUFU FUMPFUMP FUDPFUDP

ModulatorModulator

EthynyluracilEthynyluracil UracilUracil

PALAPALA

LeucovorinLeucovorinFdUDPFdUDP FdUTPFdUTPPDKPDK

FUTPFUTP

FdUMPFdUMPFUdRFUdRTSTS

TKTK

TPTP

OPRTOPRT PMKPMKPDKPDK

RRRR

PMKPMK

DPDDPD

Fluorouracil (5-FU): Metabolic Pathways Fluorouracil (5-FU): Metabolic Pathways

Adapted fromAdapted from MeropolMeropol NJ, et al.NJ, et al. SeminSemin OncolOncol. 1995;22:509. 1995;22:509--24, with permission.24, with permission.

DPD = Dihydropyrimidine dehydrogenase enzymeTS = thymidylate synthase enzyme

Examples of Drug Metabolism Pharmacogenomics, Phase 2* Examples of Drug Metabolism Pharmacogenomics, Phase 2*

Drug-Metabolizing Enzyme

Frequency of Variant Poor-Metabolism

PhenotypeRepresentative Drugs

MetabolizedEffect of

PolymorphismN-Acetyltransferase 2 52% among white

Americans; 17% of Japanese

IsoniazidHydralazineProcainamide

Enhanced drug effect

Uridine diphosphate- clucurono-syltransferase 1A1 (TATA-box polymorphism)

10.9% among whites4% of Chinese1% of Japanese

IrinotecanBilirubin

Enhanced drug effectGilberts syndrome

Thiopurine S- methyltransferase

Approximately 1 in 300 whitesApproximately 1 in 2500 Asians

MercaptopurineAzathiopuring

Enhanced drug effect (toxicity)

Catechol O- methyltransferase

Approximately 25% of whites

Levodopa Enhanced drug effect

*Examples of genetically polymorphic phase 2 (conjugating) enzymes are listed that catalyze drug metabolism, including selected examples of drugs that have clinically relevant variations in their effects.Weinshilboum R. N Engl J Med. 2003;348:529-37.

Irinotecan and UGT 1A1Irinotecan and UGT 1A1

Source: Nat Rev Cancer Nature Publishing Group

CES = Carboxylesterase

CYP = Cytochrome P450

UGT = UDP- glucuronosyltransferase,

6-MP and TPMT6-MP and TPMT

50% 50% -- 95%95%Dose Dose

ReductionReduction

TPMT = Thiopurine Methyltransferase

McLeod HL, Krynetski EY, Relling MV, Evan WE. Leukemia 2000;14:567-72.

CYP2D6 PolymorphismsCYP2D6 Polymorphisms

CYP2D6 is responsible for the metabolism of a number of different drugs Antidepressants, antipsychotics, analgesics,

cardiovascular drugs

Based on these polymorphisms, patients are phenotypically classified as: Ultrarapid metabolizers (UMs) Extensive metabolizers (EMs) Poor metabolizers (PMs)

CYP2D6 is responsible for the metabolism of CYP2D6 is responsible for the metabolism of a number of different drugsa number of different drugs Antidepressants, antipsychotics, analgesics, Antidepressants, antipsychotics, analgesics,

cardiovascular drugscardiovascular drugs

Based on these polymorphisms, patients are Based on these polymorphisms, patients are phenotypicallyphenotypically classified as:classified as: UltrarapidUltrarapid metabolizersmetabolizers ((UMsUMs)) Extensive Extensive metabolizersmetabolizers ((EMsEMs)) Poor Poor metabolizersmetabolizers ((PMsPMs))

Daly AK, Brockmoller J, Broly F et al. Pharmacogenetics 1996; 6:193-201.

CYP2D6 PhenotypesCYP2D6 Phenotypes

NEJM 2003; 348:529

Roden DM, et al. Ann Intern Med. 2006;145:749-57; Daly AK, Brockmoller J, Broly F et al. Pharmacogenetics 1996; 6:193-201.

Codeine IntoxicationCodeine Intoxication

Gasche Y, et al. N Engl J Med. 2004;351:2827-31.

NCCN Practice Guidelines; NCCN; Vers 1.2008.

Tamoxifen and CYP 2D6Tamoxifen and CYP 2D6

Tamoxifen PathwayTamoxifen Pathway

Goetz MP, et al: J Clin Oncol. 2005;23:9312-81.

Global Distribution of Major CYP2D6 Variant Alleles Global Distribution of Major CYP2D6 Variant Alleles

AlleleEnz.

Activity

Allele Frequency (%)

Cauc. EU Cauc USBlack

AmericanBlack

AfricansSaudi Arabia Japan China Turkey

*1 Normal 33-37 37-40 29-34 28-56 a 42-43 23 37

*2 Normal 22-33 26-34 30-27 11-45 a 9-13 20 35

*3 None 1

Prevalence of Genotype 2D6 in Thai Population Prevalence of Genotype 2D6 in Thai Population

Source: Prevalence in check up group at Phyathai II in 2007.

*10/*1033%

wt/*1031%

wt/wt9%

other27%

Lims HS, et al. J Clin Oncol. 2007;25:3837-45.

Clinical Implications of CYP2D6 Genotypes Predictive of Tamoxifen Pharmacokinetics in Metastatic Breast Cancer

Lims HS, et al. J Clin Oncol. 2007;25:3837-45.

Time to Disease Progression in Patients Treated with Tamoxifen

Clinical Implications of CYP2D6 Genotypes Predictive of Tamoxifen Pharmacokinetics in Metastatic Breast Cancer (Cont)

Clinical Implications of CYP2D6 Genotypes Predictive of Tamoxifen Pharmacokinetics in Metastatic Breast Cancer (Cont)

Kiyotani K, et al. Cancer Sci. 2008;99:995-9.

Clinical Implications of CYP2D6 Genotypes Predictive of Tamoxifen Pharmacokinetics in Metastatic Breast Cancer (Cont)

Clinical Implications of CYP2D6 Genotypes Predictive of Tamoxifen Pharmacokinetics in Metastatic Breast Cancer (Cont)

Impact of CYP2D6 on Recurrence

Versus *1/*1 Versus *1/*1 + *1/*10

CYP2D6 Genotype

No Event, N (%) (B = 46)

Event, N (%) (N = 12) P-value

Odds Ratio (95% CI) P-value

Odds Ratio (95% CI)

*1/*1 19 (41.3) 1 (8.3) -- 1.00 -- 1.00

*1/*10 19 (41.3) 4 (33.3) 0.35 4.00 (0.41-39.18)

*10/*10 8 (17.4) 7 (58.3) 0.0057 16.63 (1.75158.12)

0.0079 6.65 (1.68-26.38)

*1/*1: one local.*1/*10: one contralateral breast, three regional lymph nodes.*10/*10: One local, two contralateral breast, three regional lymph nodes, one osseous, and pulmonary.CI = confidence interval.Kiyotani K, et al. Cancer Sci. 2008;99:995-9.

Pharmacokinetic Interactions (Elimination) Pharmacokinetic Interactions (Elimination)

Effect ExampleABCB1

ABCG2

OATs

OATPs

Vinblastine and verapamil

Irinotecan and gefitinib

Methotrexate

Methotrexate and paclitaxel

Renal EliminationRenal Elimination

Scripture CD, et al. Nat Rev Cancer. 2006;6:546-58.

ABCB1 = ATP- binding cassette transporter (AKA P-glycoprotein (P-gp)ABCG2 = Breast cancer resistance protein (BCRP)OATs = Organic anion transporters OATPs = Organic anion-transporting polypeptides

Methotrexate and ProbenecidMethotrexate and Probenecid

With Probenecid

Without Probenecid

Aherne GW, et al. Br Med J. 1978;17:631-33.

Pharmacodynamic InteractionsPharmacodynamic Interactions

DesirableIncreased Antitumor Effect

AdditiveSynergistic

Decreased Toxicity

Undesirable (ADE)Decreased Antitumor EffectIncreased Toxicity

AdditiveSynergisticAntagonist

NeutralNo Change in Tumor Response

or Toxicity

Scripture CD et al. Nat Rev Cancer 2006; 6(7):546-558

ADE = Adverse Drug Event

Exploring Drug Interaction (Referring to case study) Exploring Drug Interaction (Referring to case study)Anticancer Agents Substrates Inducer Inhibitor

Cyclophosphamide2B6, 3A42C8, 2C92C19,2D6

2B6, 3A4, 2C8, 2C9

3A4 (weak)

Doxorubicin3A4

pGP, 2D62D6, 3A4

(weak)

Paclitaxel2C8, 3A4

pGP2C8, 3A4

(weak)

Tamoxifen 2D6, 3A4 2C8/9, pGPpGP, 3A4

(weak)

Trastuzumab n/a

Bold = major pathwayCozza, 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;546-59.a

Exploring Drug InteractionsExploring Drug Interactions

Paclitaxel + Doxorubicin Randomized, crossover study in metastatic breast cancer patients

n = 10 Dox Pac Pac Dox Mean DiffDox 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 na

Stomatitis(# patients) 1 7 na

Paclitaxel given before doxorubicin decreases dox Cl Leads to increased side effects (SEs) Mechanism PK interaction (3A4, pGP competition) Management doxorubicin 24 hrs before paclitaxel

Holmes FA, et al. J Clin Oncol. 1996;14:2713-21.

DOX Cl = Doxorubicin Clearance

Exploring Drug InteractionsExploring Drug Interactions

Chemotherapy + Trastuzumab Randomized, controlled, phase 3 clinical trial in metastatic breast cancer

patients

OutcomesCyclo/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

Slamon DJ, et al. N Engl J Med. 2001;344:783-92.

Exploring Drug InteractionsExploring Drug Interactions

Chemotherapy + Trastuzumab (contd) Mechanism

Proposed: HER-2 expression in cardiac tissues Prevailing: Cyclo/Dox cause cardiac tissue damage,

Trastuzumab impairs cellular repair time Currently unknown PD interaction

Management Risk:benefit assessment Cardiac monitoring (baseline, every 3 months)

Slamon DJ, et al. N Engl J Med. 2001;344:783-92.

HER-2 = Human epidermal growth factor receptor 2

Exploring Drug InteractionsExploring Drug Interactions

Cyclophosphamide + Aprepitant Cyclophosphamide

Effective antitumor agent Prodrug bioactivation (via CYP3A4 to 4-OH-cyclophosphamide) Autoinducer High emetogenic potential

Aprepitant (Emend) Effective for acute and delayed emesis Dosing 1hr before to several days post-chemo CYP3A4 substrate, inhibitor (moderate)

de Jonge ME, et al. Clin Pharmacokinet. 2005;44:1135-14.

Exploring Drug InteractionsExploring Drug Interactions

Cyclophosphamide + Aprepitant (contd) Clinical trial

Coadministration (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 antitumor response Modify chemo regimen as necessary Caution with use of other 3A4 inhibitors (antibiotics, antifungals)

de Jonge ME, et al. Cancer Chemother Pharmacol. 2005;56:370-78.

Exploring Drug InteractionsExploring Drug Interactions

Tamoxifen and CYP2D6 (contd)

ENDOXIFEN: 100x receptor affinity 100x potency

Effect of CYP2D6 polymorphisms on tamoxifen response???Goetz MP, et al: J Clin Oncol. 2005;23:9312-81.

Prevention of Drug InteractionsPrevention of Drug Interactions

ADR = Adverse Drug Reaction

Horn JR, Hansten PD. Sources of Error in Drug Interactions. Pharmacy Times 2004(3).

ConclusionsConclusions

Cancer patients are at particularly high risk for drug-drug interactions because their treatment commonly involves multiple medications, including Cytotoxic chemotherapy Hormonal agents Supportive care drugs

Cancer patients are at particularly high risk Cancer patients are at particularly high risk for drugfor drug--drug interactions because their drug interactions because their treatment commonly involves multiple treatment commonly involves multiple medications, including medications, including CytotoxicCytotoxic chemotherapychemotherapy Hormonal agentsHormonal agents Supportive care drugsSupportive care drugs

ConclusionsConclusions

Drug-drug interactions can be minimized by Considering the potential for interactions of

all the drugs a patient is receiving/will receive during their treatment for cancer

In addition to the intended therapeutic effects

DrugDrug--drug interactions can be minimized drug interactions can be minimized by by Considering the potential for interactions of Considering the potential for interactions of

all the drugs a patient is receiving/will all the drugs a patient is receiving/will receive during their treatment for cancerreceive during their treatment for cancer

In addition to the intended therapeutic In addition to the intended therapeutic effects effects

ConclusionsConclusions

The optimal regimen would provide a combination of Good antitumor efficacy Simple administration and A low risk of drug-drug interactions

The optimal regimen would provide a The optimal regimen would provide a combination of combination of Good antitumor efficacyGood antitumor efficacy Simple administration and Simple administration and A low risk of drugA low risk of drug--drug interactionsdrug interactions

Drug Interactions in Oncology:Which Interactions Really Matter?Learning ObjectivesDisclosureCaseCase (cont.)What Could Be a Potential DRP?Drug InteractionsIntroductionPolypharmacyIntroduction (cont)Introduction (cont)Introduction (cont)PolypharmacyIncidence Related to Concomitant DrugsWhy Is it Important?Frequency and SeverityMechanism of Identified Potential Drug InteractionsTypes of Drug InteractionsPharmaceutical InteractionsPharmacokinetic InteractionsPharmacokinetic Interactions (Absorption)6-MP and AllopurinolEffect of Food on Oral Anticancer AgentsEffect of Food on Oral Anticancer AgentsEffect of Food on Oral Anticancer AgentsEffect of Food on Oral Anticancer AgentsPharmacokinetic Interactions (Distribution)Pharmacokinetic Interactions (Metabolism)Pharmacokinetic Interactions (Metabolism)Irinotecan and CYP 3A4 InducerHerbal Supplements: SJWHAARTImatinibInterpatient VariabilityDrug Metabolizing EnzymesExamples of Drug Metabolism Pharmacogenomics, Phase 1*Fluorouracil (5-FU): Metabolic PathwaysExamples of Drug Metabolism Pharmacogenomics, Phase 2* Irinotecan and UGT 1A16-MP and TPMTCYP2D6 PolymorphismsCYP2D6 PhenotypesCodeine IntoxicationTamoxifen and CYP 2D6Tamoxifen PathwayGlobal Distribution of Major CYP2D6 Variant AllelesPrevalence of Genotype 2D6 in Thai Population Slide Number 48Clinical Implications of CYP2D6 Genotypes Predictive of Tamoxifen Pharmacokinetics in Metastatic Breast Cancer(Cont)Clinical Implications of CYP2D6 Genotypes Predictive of Tamoxifen Pharmacokinetics in Metastatic Breast Cancer(Cont)Slide Number 51Pharmacokinetic Interactions (Elimination)Methotrexate and ProbenecidPharmacodynamic InteractionsExploring Drug Interaction (Referring to case study)Exploring Drug InteractionsExploring Drug InteractionsExploring Drug InteractionsExploring Drug InteractionsExploring Drug InteractionsExploring Drug InteractionsPrevention of Drug InteractionsConclusionsConclusionsConclusions