Page 1

Clinical Pharmacology of Anti-cancer Chemotherapeutic Agents www.indiandentalacademy.com


INDIAN DENTAL ACADEMY Leader in continuing dental education www.indiandentalacademy.com

www.indiandentalacademy.com


Therapeutic Principles

Diagnosis & Drug Selection

I N P U T

Absorption Distribution Metabolism Elimination

Pharmacokinetics

www.indiandentalacademy.com

Toxicity &/OR Efficacy

Pharmacodynamics


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 www.indiandentalacademy.com


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! www.indiandentalacademy.com


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” ? www.indiandentalacademy.com


Concentration

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

6

12 Time www.indiandentalacademy.com

18

24


Concentration

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

6

12 Time

www.indiandentalacademy.com

18

24


Concentration

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

6

12 Time www.indiandentalacademy.com

18

24


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

www.indiandentalacademy.com


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)

www.indiandentalacademy.com


Activation Hepatic 

e.g. cyclophosphamide, doxorubicin, daunorubicin, others

Intracellular phosphorylation 

e.g fludarabine

Tissue metabolism with free radical production 

e.g. doxorubicin

www.indiandentalacademy.com


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 www.indiandentalacademy.com


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)

www.indiandentalacademy.com


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

www.indiandentalacademy.com


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 www.indiandentalacademy.com


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.

www.indiandentalacademy.com


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

www.indiandentalacademy.com


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…

www.indiandentalacademy.com


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) www.indiandentalacademy.com

50

60

70


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.

www.indiandentalacademy.com


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

www.indiandentalacademy.com


Oral Chemotherapy Alkylating Agents  

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

 

busolfan (Myleran) procarbazine (Mutalane)

www.indiandentalacademy.com


Oral Chemotherapy Antimetabolites ď Ž

capecitabine (Xeloda) Oral pro-drug version of fluorouracil

ď Ž

Mercaptopurine (Purinethiol) Variable and incomplete absorption

www.indiandentalacademy.com


Oral Chemotherapy Hormonal Oncologics 

Tamoxifen

Mitosis Inhibitors 

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

Others 

Hydroxurea Well aborbed

www.indiandentalacademy.com


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

www.indiandentalacademy.com


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.

www.indiandentalacademy.com


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’ www.indiandentalacademy.com


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) www.indiandentalacademy.com


Dose Form Manipulation Chemoembolization ď Ž

Arterial infusion of methylcellulose microcapsules filled with chemotherapeutics

Implantable polymers ď Ž

Surgical implantation of biodegradable polymers containing chemotherapeutics

www.indiandentalacademy.com


www.indiandentalacademy.com Leader in continuing dental education

www.indiandentalacademy.com

Chemotherapeutic agents pharmacology/ dental implant courses by Indian dental academy  

The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and offering a wide r...

Read more
Read more
Similar to
Popular now
Just for you