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1. Clinical Pharmacology of
Anti-cancer
Chemotherapeutic
Agents
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2. INDIAN DENTAL ACADEMY
Leader in continuing dental education
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3. Therapeutic Principles
Diagnosis
&
Drug
Selection
I
N
P
U
T
Absorption
Distribution
Metabolism
Elimination
Pharmacokinetics
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Toxicity
&/OR
Efficacy
Pharmacodynamics

4. Therapeutic Endpoints
Efficacy without toxicity


Human medicine: palliative therapy only
Veterinary medicine: palliative therapy probably?
Efficacy AND toxicity

Human and veterinary medicine: aggressive, curative therapy
Toxicity without efficacy

Tentative administration
You may affect bone marrow ONLY rather than bone marrow AND
tumor

Drug Resistance
Reduces tumor response, bone marrow still sensitive
Neither toxicity nor efficacy
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5. Dosing v. P’kinetic End Points
EITHER

mg/kg (/M2) X interval X duration
OR


Peak drug concentration, AUC
(Concentration X Time), Time above
target concentration, Cumulative dose,
Cumulative AUC
WHICH one depends on drug.
Base choice on clinical trials!
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6. Dose vs AUC Target
Nagahiro Saijo, Chemotherapy: the more the better? Overview, Cancer Chemother Pharmacol (1997) 40
(Suppl): S100– S106
These are the SAME PATIENTS. What separates them on the Graph labeled
“A” ?
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7. Concentration
Peak Concentration
90
80
70
60
50
40
30
20
10
0
0
6
12
Time
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18
24

8. Concentration
AUC
90
80
70
60
50
40
30
20
10
0
0
6
12
Time
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18
24

9. Concentration
Intensity / Time Above
90
80
70
60
50
40
30
20
10
0
0
6
12
Time
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18
24

10. Absorption
Oral


Variable concentration X time profile
Typical factors affecting oral absorption
Presence of food
Concurrent disease

Likely produces a different efficacy / toxicity
profile
Etopside oral vs. IV
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11. Absorption
Intramuscular

VERY few anti-cancer drugs can be given this
way
Cytotoxicity associated with tissue damage at
injection site

Used by this route:
Hormones (glucocorticoids, leuprolide)
L-asparaginase (lower toxicity than IV)
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12. Activation
Hepatic

e.g. cyclophosphamide, doxorubicin,
daunorubicin, others
Intracellular phosphorylation

e.g fludarabine
Tissue metabolism with free radical
production

e.g. doxorubicin
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13. Distribution
Most target intra-cellular sites

Combination solubility (water:lipid)
Small number penetrate blood-brain
barrier
Protein binding


High protein binding increases interaction
potential
May or may not limit tissue “penetration”
Consider both plasma and tissue proteins
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14. Distribution
Active Metabolite distribution

Ifosfamide metabolites cross blood-brain
barrier
Consider local factors


Tumor vascularity
P-glycoprotein cell membrane pump
(drug efflux pump – something like antibiotic
resistance by bacteria)
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15. Elimination
Hepatic Metabolism

P450 metabolism
Catabolism (especially anti-metabolites)

Normal degradation pathways for amino acids
etc. to carbon dioxide and water
Hydrolysis
Renal elimination unchanged
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16. Dosing Chemotherapeutics
What are we really doing in veterinary
patients?




Dosing for palliation in most cases
Critiquing dose regimes with more emphasis
on toxicity than efficacy
Specifics of the approach to dosing become
more important as the therapy becomes more
aggressive.
We should formulate clear and specific
therapeutic goals
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17. Dosing Chemotherapeutics
Body surface area
mg/kg
Total dose
Dose to pharmacokinetic target


AUC, Peak, etc.
Therapeutic monitoring laboratory capability
required.
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18. Dosing Chemotherapeutics
Traditional dosing on Body Surface Area


Correlates with metabolic rate, volume of
distribution
Correlation with tissue concentrations?
Efficacy and toxicity


Extrapolated (with enthusiasm from human
dose recommendations)
Probably correct for SOME but not ALL
protocols
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19. Body Surface Area
Dogs
10 × ( bw in grams )
10,000
Cats
10.1× ( bw in grams )
10,000
2/3
2/3
These are approximations.

Man/Woman – 5 formulas, all include height, some
gender, some age…
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20. Body Surface Area
BSA Nomogram
1.8
Meters Squared
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
0
10
20
30
40
Weight (kg)
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50
60
70

21. Body Surface Area
Arrington et al. AJVR 55(11) 1587-92

30 mg/M2 Adriamycin
Dogs <10 kg received more than 1.5 mg/kg

Increased incidence of toxicity
Dogs >10 kg received less than 1.0 mg/kg


Study did not evaluate differential efficacy
Potential for breed-related differences in
toxicity.
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22. Oral Chemotherapy
Widely used in Veterinary Chemotherapy



Concerns for patient “discomfort”
Infrequent use of “indwelling” lines
Palliation is primary goal
High peak concentrations or large AUC are not a
concern
Dosing control is not as critical
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23. Oral Chemotherapy
Alkylating Agents


melphalon (Alkeran)
cyclophosphamide (Cytoxan)
Excellent absorption characteristics
Most widely used (therefore most experience)
Oncology, immunology uses


busolfan (Myleran)
procarbazine (Mutalane)
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24. Oral Chemotherapy
Antimetabolites

capecitabine (Xeloda)
Oral pro-drug version of fluorouracil

Mercaptopurine (Purinethiol)
Variable and incomplete absorption
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25. Oral Chemotherapy
Hormonal Oncologics

Tamoxifen
Mitosis Inhibitors

Etopside (VP16, Vepised)
Variable dose-dependent oral bioavailability
Others

Hydroxurea
Well aborbed
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26. IM Chemotherapy
aspariginase (Elspar)

IM is thought to produce fewer allergic
reactions
Not confirmed with large number of cases
leuprolide (Lupron)

Short acting GnRH Agonist
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27. Intravenous Chemotherapy
Why?



Drugs, and sometimes vehicles, too irritating
(cytotoxic) by other routes
Produce high peak concentration
OPPORTUNITY to exert extreme control over
plasma concentrations.
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28. Gemcitabine
Controlled intravenous infusion


Metabolism to active compounds is saturable
Rates of administration exceeding conversion
capability waste drug
e.g., Un-converted gemcitabine is eliminated in the
urine.

Rates of administration exceeding conversion
produce less activity per milligram of drug.
10 mg given slowly -> ‘10 mg of activity’
10 mg given rapidly -> ‘8 mg of activity’
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29. Dose Form Manipulation
Liposomes

Drug contained in lipid spheres
Essentially artificial liposomal membranes
Actively acquired by some cell lines

Improved therapeutic index
Reduced cardiotoxicity
Enhanced activity
(although certain other toxicities may be
enhanced)
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30. Dose Form Manipulation
Chemoembolization

Arterial infusion of methylcellulose microcapsules filled with chemotherapeutics
Implantable polymers

Surgical implantation of biodegradable
polymers containing chemotherapeutics
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31. www.indiandentalacademy.com
Leader in continuing dental education
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