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Clinical Pharmacology of Anti-cancer Chemotherapeutic Agents

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Therapeutic Principles

Diagnosis & Drug Selection


Absorption Distribution Metabolism Elimination


Toxicity &/OR Efficacy


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

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!

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” ?


Peak Concentration 90 80 70 60 50 40 30 20 10 0 0


12 Time




AUC 90 80 70 60 50 40 30 20 10 0 0


12 Time




Intensity / Time Above 90 80 70 60 50 40 30 20 10 0 0


12 Time



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

Absorption Intramuscular ď Ž

VERY few anti-cancer drugs can be given this way Cytotoxicity associated with tissue damage at injection site

ď Ž

Used by this route: Hormones (glucocorticoids, leuprolide) L-asparaginase (lower toxicity than IV)

Activation Hepatic 

e.g. cyclophosphamide, doxorubicin, daunorubicin, others

Intracellular phosphorylation 

e.g fludarabine

Tissue metabolism with free radical production 

e.g. doxorubicin

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

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)

Elimination Hepatic Metabolism ď Ž

P450 metabolism

Catabolism (especially anti-metabolites) ď Ž

Normal degradation pathways for amino acids etc. to carbon dioxide and water

Hydrolysis Renal elimination unchanged

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

Dosing Chemotherapeutics Body surface area mg/kg Total dose Dose to pharmacokinetic target ď Ž ď Ž

AUC, Peak, etc. Therapeutic monitoring laboratory capability required.

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

Body Surface Area Dogs

10 × ( bw in grams ) 10,000


10.1× ( bw in grams ) 10,000



These are approximations. 

Man/Woman – 5 formulas, all include height, some gender, some age…

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





Weight (kg)




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.

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

Oral Chemotherapy Alkylating Agents  

melphalon (Alkeran) cyclophosphamide (Cytoxan) Excellent absorption characteristics Most widely used (therefore most experience) Oncology, immunology uses

 

busolfan (Myleran) procarbazine (Mutalane)

Oral Chemotherapy Antimetabolites ď Ž

capecitabine (Xeloda) Oral pro-drug version of fluorouracil

ď Ž

Mercaptopurine (Purinethiol) Variable and incomplete absorption

Oral Chemotherapy Hormonal Oncologics 


Mitosis Inhibitors 

Etopside (VP16, Vepised) Variable dose-dependent oral bioavailability

Others 

Hydroxurea Well aborbed

IM Chemotherapy aspariginase (Elspar) ď Ž

IM is thought to produce fewer allergic reactions Not confirmed with large number of cases

leuprolide (Lupron) ď Ž

Short acting GnRH Agonist

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.

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’

Dose Form Manipulation Liposomes ď Ž

Drug contained in lipid spheres Essentially artificial liposomal membranes Actively acquired by some cell lines

ď Ž

Improved therapeutic index Reduced cardiotoxicity Enhanced activity (although certain other toxicities may be enhanced)

Dose Form Manipulation Chemoembolization ď Ž

Arterial infusion of methylcellulose microcapsules filled with chemotherapeutics

Implantable polymers ď Ž

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Chemotherapeutic agents pharmacology/ dental implant courses by Indian dental academy  
Chemotherapeutic agents pharmacology/ dental implant courses by Indian dental academy  

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