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Drug Interactions in Oncology:

Which Interactions Really Matter?

Suphat
Suphat Subongkot,
Subongkot, PharmD,
PharmD,
BCPS,
BCPS, BCOP
BCOP
Assistant
Assistant Professor
Professor
Pharmacy
Pharmacy Practice
Practice Division
Division
Khon
Khon Kaen
Kaen University
University
Khon
Khon Kaen,
Kaen, Thailand
Thailand

Learning Objectives

Describe the principles of drug


interactions

List common drug interactions in oncology

Explain the impact of drug interactions in


cancer care

Disclosure

Suphat Subongkot, PharmD, BCPS,


BCOP has no real or apparent conflicts of
interest to report

Case

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.)
Allergy: NKDA
Home medications:

Albuterol + ipratropium 2 puffs qid


Omeprazole 30 mg bid
Medication on admission:

Adriamycin + paclitaxel + trastuzumab


Tamoxifen
Omeprazole
Ondasetron + aprepitant + dexamethasone
Sertraline

What Could Be a Potential DRP?

DRP = Drug-related problem

Drug Interactions
CHEMO DRUG

Efficacy
Toxicity
CHEMO-RELATED
DRUG

NON-CANCER
RELATED DRUG

Introduction

Patients with cancer are at considerable


risk of drug interactions due to
A large number of drugs during their
treatment

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

Polypharmacy
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)
Complementary Alternative Medicines

51.6% of patients with cancer were taking


complementary alternative medicines
12.2% were subsequently issued a health
warning

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

Introduction (cont)
Aging Population

Approximately 60% of patients with cancer are


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)
Aging Population

78% of patients over 65 years of age are


taking prescription medications
39% regularly take five or more drugs

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

Polypharmacy
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
Number of
Drugs

Estimated (%)

Actual (%)

5.6

5.6

16.8

15.8

33.6

34.3

56

46.7

84

72

100

66

100

100

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

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

Frequency and Severity


Variable

No.

No. of patients participated

405

100

No. of patients with potential DI

109

27

No. of potential DI indentified

276

100

Major

25

Moderate

84

77

Minor

100

14

Severity of drug interactions

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

Mechanism of Identified Potential Drug


Interactions
Variable (N = 405)

No.

276

100

Pharmacokinetic

151

55

Pharmacodynamic

70

25

Unknown

55

20

No. of potential drug interactions


Mechanism of identified potential DI

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

Types of Drug Interactions

Pharmaceutical interactions

Pharmacokinetic interactions

Pharmacodynamic interactions

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

Pharmaceutical Interactions
Incompatibility either physically or chemically
Drug 1
Mesna

Mitomycin

Drug 2

Outcomes

Cisplatin

A covalent
mesna-platinum
adduct

D5W (pH 4-5)

Inactive
mitosenes

Some IV fluids

Precipitation

Taxanes
Etoposide

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

Pharmacokinetic Interactions
Absorption
Distribution
Metabolism
Excretion

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

Pharmacokinetic Interactions
(Absorption)
Areas for potential drug interactions
Effect

Altered absorption

Example

Allopurinol and 6-MP

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 Allopurinol

With allopurinol

Allopurinol 100 mg
tid x 2 day
6-MP 75 mg PO

Without
allopurinol

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

Effect of Food on Oral


Anticancer Agents
Drug

Effect of Food

PK Parameters

Busulfan
5-FU
Methotrexate

Delayed
absorption
(effect on rate)

Change in Cmax
and Tmax

Topotecan
Cmax = Maximum Plasma Concentration
Tmax = Time to Maximum Plasma Concentration

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 .

Effect of Food on Oral


Anticancer Agents
Drug

Effect of Food

PK Parameters

Altretamine
Capecitabine
Chlorambucil
Estramustine
Gefitinib

Delayed
absorption
(effect on extent)

Change in AUC
and Cmax

Melphalan
Thioguanine
AUC= Area under the plasma (serum, or blood) concentration versus time curve
Cmax = Maximum Plasma Concentration
Scripture CD, Figg WD. Nat Rev Cancer. 2006;6:546-88.

Effect of Food on Oral


Anticancer Agents
Drug

Erlotinib
Tretinoin

Effect of Food

PK Parameters

Increased
absorption (effect
on extent and/or
rate)

Increase in AUC
and usually Cmax
and/or Tmax

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

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

Effect of Food on Oral


Anticancer Agents
Drug
Etoposide

Effect of Food

Imatinib

Unaffected
absorption

Mercaptopurine

(No effect on rate

Temozolomide

or extent)

PK Parameters

No significant
change in AUC and
Cmax

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

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

Pharmacokinetic Interactions
(Distribution)
Areas for potential drug interactions
Effect

Highly protein-bound

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

Example

Paclitaxel and etoposide

Pharmacokinetic Interactions
(Metabolism)
Areas for potential drug interactions
Effect

Increased metabolism

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

Example

Anticonvulsants and irinotecan

Pharmacokinetic Interactions
(Metabolism)
Hepatic Metabolism
CYP 3A4

Example Drugs
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 Inducer


CPT-11= Irinotecan
SN-38 = Irinotecan active
metabolite

CES = Carboxylesterase
CYP = Cytochrome P450
UGT = UDP-glucuronosyltransferase,

Source: Nat Rev Cancer Nature Publishing Group

Herbal Supplements: SJW

SJW = St. Johns wort

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

HAART
Areas for potential drug interactions
Effect

Example

CYP system
Substrates
Protease Inhibitors (PIs)
Inhibitors
NNRTIs
Inducers
ABCB1 (ATP-binding cassette)

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

Imatinib
Drug

Effect

Mechanism

Mgmt

Opiates

Increase sedation
(common)

CYP2D6
inhibition

Decrease
dose

Statins

Increased
rhabdomyolysis
(rare)

CYP3A4
inhibition

Warfarin

Increased bleeding

CYP3A4
inhibition

Monitor
signs of
weakness,
lethargy
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 Variability

Evidence of an inherited basis for drug


response dates back in the literature to the
1950s
Succinylcholine
Succinylcholine:: 1 in 3000 patients developed
prolonged muscle relaxation

Monogenic

Phenotype 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 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*
Drug-Metabolizing
Enzyme
Cytochrome P-450 2D6
(CYP2D6)

Frequency of Variant
Poor-Metabolism
Phenotype

Representative Drugs
Metabolized

Effect of Polymorphism

6.7% in Sweden

Debrisoquin

Enhanced drug effect

1% in China

Sparteine

Enhanced drug effect

Nortriptyline

Enhanced drug effect

Codeine

Decreased drug effect

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

Warfarin

Enhanced drug effect

Omeprazole

Enhanced drug effect

(CYP2C19)

2.7% among white


Americans; 3.3% in
Sweden; 14.6% in China;
18% in Japan

Dihydropyrimidine
dehydrogenase

Approximately 1% of
population is heterozygous

Fluorouracil

Enhanced drug effect

Butyrylcholinesterase
(pseudocholinesterase)

Approximately 1 in 3500
Europeans

Succinylcholine

Enhanced drug effect

Cytochrome P-450 2C9


(CYP2C9)

Cytochrome P-450 2C19

Phenytoin

*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.

Fluorouracil (5-FU): Metabolic


Pathways

DPD
FUTP
PDK
OPRT
PMK
FUMP
FUDP

5-FU

RR
FdUDP

TP

PDK

PMK
FUdR

TK

FdUMP

Ultimate Fate

Modulator

Inactive
metabolite

Ethynyluracil
Uracil

Abnormal
RNA
synthesis

PALA

Inhibit DNA
Leucovorin
FdUTP
synthesis
through
inhibition of TS

TS

DPD = Dihydropyrimidine dehydrogenase enzyme


TS = thymidylate synthase enzyme
Adapted from Meropol NJ, et al. Semin Oncol.
Oncol. 1995;22:5091995;22:509-24, with permission.

Examples of Drug Metabolism


Pharmacogenomics, Phase 2*
Drug-Metabolizing
Enzyme

Frequency of Variant
Poor-Metabolism
Phenotype

Representative Drugs
Metabolized

Effect of
Polymorphism

52% among white


Americans; 17% of
Japanese

Isoniazid

Uridine diphosphateclucurono-syltransferase
1A1 (TATA-box
polymorphism)

10.9% among whites

Irinotecan

Enhanced drug effect

4% of Chinese

Bilirubin

Gilberts syndrome

Thiopurine Smethyltransferase

Approximately 1 in 300
whites

Mercaptopurine
Azathiopuring

Enhanced drug effect


(toxicity)

Levodopa

Enhanced drug effect

N-Acetyltransferase 2

Enhanced drug effect

Hydralazine
Procainamide

1% of Japanese

Approximately 1 in 2500
Asians
Catechol Omethyltransferase

Approximately 25% of
whites

*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 1A1

CES = Carboxylesterase
CYP = Cytochrome P450
UGT = UDPglucuronosyltransferase,

Source: Nat Rev Cancer Nature Publishing Group

6-MP and TPMT


TPMT = Thiopurine Methyltransferase

50% - 95%
Dose
Reduction

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

CYP2D6 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)


UMs)
Extensive metabolizers ((EMs)
EMs)
Poor metabolizers ((PMs)
PMs)

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

CYP2D6 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 Intoxication

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

Tamoxifen and CYP 2D6

NCCN Practice Guidelines; NCCN; Vers 1.2008.

Tamoxifen Pathway

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

Global Distribution of Major CYP2D6


Variant Alleles
Allele Frequency (%)
Allele

Enz.
Activity

Cauc. EU

Cauc US

Black
American

Black
Africans

Saudi
Arabia

Japan

China

Turkey

*1

Normal

33-37

37-40

29-34

28-56

42-43

23

37

*2

Normal

22-33

26-34

30-27

11-45

9-13

20

35

*3

None

<2

<1

<1

*4

None

12-23

18-23

7-9

1-7

<1

0-1

11

*5

None

2-7

2-4

6-7

1-6

<1

5-6

15

*6

None

<2

<1

*9

Redcd

0-3

2-3

<1

<1

*10

Redcd

1-2

4-8

3-8

3-9

<1

39-41

50-70

*17

Redcd

<1

15-26

9-34

<1

<1

*41

Redcd

20

*1xN

Incrsd

<1

<1

<1

<1

*2xN

Incrsd

<2

<1

10

<1

<1

*4xN

None

<1

<1

<1

a= No data reported.
Ingelman Sundburg M, Oscason M, Daly AK et al. Cancer Epidemiol Biomarkers Prev 2001; 10:1307-8; Daly AK, Brockmoller J,
Broly F et al. Pharmacogenetics 1996; 6:193-201; AmpliChip Package Insert, Roche Diagnostics, 2006.

Prevalence of Genotype 2D6


in Thai Population
other
27%

wt/wt
9%
wt/*10
31%

*10/*10
33%

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

Clinical Implications of CYP2D6 Genotypes Predictive of


Tamoxifen Pharmacokinetics in Metastatic Breast Cancer

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

Clinical Implications of CYP2D6 Genotypes Predictive of


Tamoxifen Pharmacokinetics in Metastatic Breast Cancer
(Cont)
Time to Disease Progression in Patients Treated with Tamoxifen

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

Clinical Implications of CYP2D6 Genotypes Predictive of


Tamoxifen Pharmacokinetics in Metastatic Breast Cancer
(Cont)

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

Impact of CYP2D6 on Recurrence


Versus *1/*1
CYP2D6
Genotype

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

Event, N (%)
(N = 12)

P-value

Odds Ratio
(95% CI)

*1/*1

19 (41.3)

1 (8.3)

--

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)

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

P-value

Odds Ratio
(95% CI)

--

1.00

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)
Renal Elimination
Effect

Example

ABCB1

Vinblastine and verapamil

ABCG2

Irinotecan and gefitinib

OATs
OATPs

Methotrexate
Methotrexate and paclitaxel

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

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

Methotrexate and Probenecid

With Probenecid

Without Probenecid

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

Pharmacodynamic Interactions

Desirable
Increased Antitumor Effect
Additive
Synergistic
Decreased Toxicity

Undesirable (ADE)
Decreased Antitumor Effect
Increased Toxicity
Additive
Synergistic
Antagonist

Neutral
No Change in Tumor Response
or Toxicity

ADE = Adverse Drug Event


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

Exploring Drug Interaction


(Referring to case study)
Anticancer Agents

Substrates

Inducer

Inhibitor

Cyclophosphamide

2B6, 3A4
2C8, 2C9
2C19,2D6

2B6, 3A4,
2C8, 2C9

3A4 (weak)

Doxorubicin

3A4
pGP, 2D6

Paclitaxel

2C8, 3A4
pGP

Tamoxifen

2D6, 3A4
2C8/9, pGP

Trastuzumab

2D6, 3A4
(weak)
2C8, 3A4
(weak)
pGP, 3A4
(weak)
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;546-59.a

Exploring Drug Interactions


Paclitaxel + Doxorubicin

Randomized, crossover study in metastatic breast cancer patients


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

na

Stomatitis
(# patients)

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

DOX Cl = Doxorubicin Clearance


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

Exploring Drug Interactions


Chemotherapy + Trastuzumab

Randomized, controlled, phase 3 clinical trial in metastatic breast cancer


patients
Cyclo/Dox
(n = 135)

Cyclo/Dox +
Trastuzumab
(n = 143)

Response (%)

58

80

Cardiotox (%)

27

Outcomes

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 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)

HER-2 = Human epidermal growth factor receptor 2


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

Exploring 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 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 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 Interactions

ADR = Adverse Drug Reaction


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

Conclusions

Cancer patients are at particularly high risk


for drug
-drug interactions because their
drug-drug
treatment commonly involves multiple
medications, including
Cytotoxic chemotherapy

Hormonal agents
Supportive care drugs

Conclusions

Drug
-drug interactions can be minimized
Drug-drug
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

Conclusions

The optimal regimen would provide a


combination of
Good antitumor efficacy

Simple administration and


A low risk of drug
-drug interactions
drug-drug

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