Clinical Pharmacology of AntiAnti-cancer Chemotherapeutic Agents

Dr. Jeff R. Wilcke

Therapeutic Principles
I N P U T

Diagnosis & Drug Selection

Absorption Distribution Metabolism Elimination

Toxicity &/OR Efficacy

Pharmacokinetics

Pharmacodynamics

Therapeutic Endpoints
Efficacy without toxicity
 

Human medicine: palliative therapy only Veterinary medicine: palliative therapy probably? Human and veterinary medicine: aggressive, curative therapy Tentative administration
You may affect bone marrow ONLY rather than bone marrow AND tumor

Efficacy AND toxicity



Toxicity without efficacy



Drug Resistance
Reduces tumor response, bone marrow still sensitive

Neither toxicity nor efficacy

Dosing v. Pkinetic End Points

EITHER


mg/kg (/M2) X interval X duration Peak drug concentration, AUC (Concentration X Time), Time above target concentration, Cumulative dose, Cumulative AUC WHICH one depends on drug.

OR


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 6 12 Time 18 24

Concentration

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

Concentration

Intensity / Time Above

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

Absorption
Oral
 

Variable concentration X time profile Typical factors affecting oral absorption

Presence of food Concurrent disease

Likely produces a different efficacy / toxicity profile

Absorption
Intramuscular


VERY few anti-cancer drugs can be given this antiway

Cytotoxicity associated with tissue damage at injection site

Used by this route:

Hormones (glucocorticoids, leuprolide) L-asparaginase (lower toxicity than IV)

Activation
Hepatic


e.g. cyclophosphamide, doxorubicin, daunorubicin, others e.g fludarabine

Intracellular phosphorylation


Tissue metabolism with free radical production



e.g. doxorubicin

Distribution
Most target intra-cellular sites intra

Combination solubility (water:lipid) (water:lipid)

Very few penetrate blood-brain barrier bloodProtein 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 bloodbarrier Tumor vascularity

Tumor may outgrow blood supply Interaction with angiogenesis inhibitors?

Consider local factors



P-glycoprotein cell membrane pump

drug efflux pump (something like antibiotic resistance by bacteria)

Elimination
Hepatic Metabolism


P450 metabolism Normal degradation pathways for amino acids etc. to carbon dioxide and water

Catabolism (especially anti-metabolites) anti

Hydrolysis Renal elimination unchanged (what does this mean for owner safety?)

Dosing Chemotherapeutics
What are we really doing in veterinary patients?


Critiquing dose regimes with more emphasis on toxicity than efficacy

So were dosing for palliation in most cases?

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
 

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 v bw in grams 10,000

2/3

Cats

10.1v bw in grams 10,000

2/3

These are approximations.



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

Body Surface Area

BSA Nomogram
1.8 1.6 1.4

Meters Squared

1.2 1 0.8 0.6 0.4 0.2 0 0 10 20 30 40 50 60 70 Weight (kg)

Body Surface Area

Arrington et al. AJVR 55(11) 1587-92 1587

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 breedtoxicity This sort of study ->
alter BSA formulas? Switch to mg/kg dosing?

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


cyclophosphamide (Cytoxan) Cytoxan)

Excellent absorption characteristics Most widely used (therefore most experience) Oncology, immunology uses

  

melphalon (Alkeran) Alkeran) busolfan (Myleran) Myleran) procarbazine (Mutalane) Mutalane)

Oral Chemotherapy
Antimetabolites


capecitabine (Xeloda)
Oral pro-drug version of fluorouracil pro-

Mercaptopurine (Purinethiol)
Variable and incomplete absorption

Oral Chemotherapy
Hormonal Oncologics


Tamoxifen Etoposide (VP16, Vepesed) Vepesed)

Variable dose-dependent oral bioavailability dose-

Mitosis Inhibitors


Others


Hydroxurea
Well aborbed

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

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 may be saturable

Rates of administration that saturate conversion rate waste drug


e.g., Un-converted gemcitabine is eliminated in the urine. Un-

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


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)

Dose Form Manipulation

Chemoembolization


Arterial infusion of methylcellulose micromicrocapsules filled with chemotherapeutics Surgical implantation of biodegradable polymers containing chemotherapeutics

Implantable polymers