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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
Disclosure
Case
Case (cont.)
Allergy: NKDA
Home medications:
Drug Interactions
CHEMO DRUG
Efficacy
Toxicity
CHEMO-RELATED
DRUG
NON-CANCER
RELATED DRUG
Introduction
Polypharmacy
Chemotherapy Agents
Cyclophosphamide (Cytoxan)
Doxorubicin (Adriamycin)
Paclitaxel (Taxol)
Tamoxifen (Nolvadex)
Trastuzumab (Herceptin)
Supportive Care
Introduction (cont)
Complementary Alternative Medicines
Introduction (cont)
Aging Population
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
Polypharmacy
Other Medical Conditions
Estimated (%)
Actual (%)
5.6
5.6
16.8
15.8
33.6
34.3
56
46.7
84
72
100
66
100
100
Why Is it Important?
Combined illnesses
Adverse effects of antineoplastic agents
No.
405
100
109
27
276
100
Major
25
Moderate
84
77
Minor
100
14
DI = drug interaction
Rachel P, et al. J Natl Cancer Inst. 2007;99:592-600.
No.
276
100
Pharmacokinetic
151
55
Pharmacodynamic
70
25
Unknown
55
20
Pharmaceutical interactions
Pharmacokinetic interactions
Pharmacodynamic interactions
Pharmaceutical Interactions
Incompatibility either physically or chemically
Drug 1
Mesna
Mitomycin
Drug 2
Outcomes
Cisplatin
A covalent
mesna-platinum
adduct
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
Pharmacokinetic Interactions
(Absorption)
Areas for potential drug interactions
Effect
Altered absorption
Example
6-MP = 6-Mercaptopurine
Lennard L. Eur J Clin Pharmacol 1992; 43:329-339; Poplack DG, et al. Cancer 1986; 58: 437-480
With allopurinol
Allopurinol 100 mg
tid x 2 day
6-MP 75 mg PO
Without
allopurinol
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
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.
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
Effect of Food
Imatinib
Unaffected
absorption
Mercaptopurine
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
Pharmacokinetic Interactions
(Distribution)
Areas for potential drug interactions
Effect
Highly protein-bound
Example
Pharmacokinetic Interactions
(Metabolism)
Areas for potential drug interactions
Effect
Increased metabolism
Example
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
CES = Carboxylesterase
CYP = Cytochrome P450
UGT = UDP-glucuronosyltransferase,
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
Monogenic
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.
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.
Frequency of Variant
Poor-Metabolism
Phenotype
Representative Drugs
Metabolized
Effect of Polymorphism
6.7% in Sweden
Debrisoquin
1% in China
Sparteine
Nortriptyline
Codeine
Approximately 3% in
England (those
homozygous for the *2
and *3 alleles)
Warfarin
Omeprazole
(CYP2C19)
Dihydropyrimidine
dehydrogenase
Approximately 1% of
population is heterozygous
Fluorouracil
Butyrylcholinesterase
(pseudocholinesterase)
Approximately 1 in 3500
Europeans
Succinylcholine
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.
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
Frequency of Variant
Poor-Metabolism
Phenotype
Representative Drugs
Metabolized
Effect of
Polymorphism
Isoniazid
Uridine diphosphateclucurono-syltransferase
1A1 (TATA-box
polymorphism)
Irinotecan
4% of Chinese
Bilirubin
Gilberts syndrome
Thiopurine Smethyltransferase
Approximately 1 in 300
whites
Mercaptopurine
Azathiopuring
Levodopa
N-Acetyltransferase 2
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.
CES = Carboxylesterase
CYP = Cytochrome P450
UGT = UDPglucuronosyltransferase,
50% - 95%
Dose
Reduction
McLeod HL, Krynetski EY, Relling MV, Evan WE. Leukemia 2000;14:567-72.
CYP2D6 Polymorphisms
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
Tamoxifen Pathway
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.
wt/wt
9%
wt/*10
31%
*10/*10
33%
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)
P-value
Odds Ratio
(95% CI)
--
1.00
0.0079
6.65
(1.68-26.38)
Pharmacokinetic Interactions
(Elimination)
Renal Elimination
Effect
Example
ABCB1
ABCG2
OATs
OATPs
Methotrexate
Methotrexate and paclitaxel
With Probenecid
Without Probenecid
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
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
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
Cyclo/Dox +
Trastuzumab
(n = 143)
Response (%)
58
80
Cardiotox (%)
27
Outcomes
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)
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)
ENDOXIFEN:
100x receptor affinity
100x potency
Conclusions
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
Conclusions