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Transcript
Clinical Pharmacology
Lillian Siu
Role of chemotherapy
• Curative therapy
–  survival
• Palliative therapy
–  quality of life, clinical benefit
• Adjuvant therapy
– Neoadjuvant: downstaging
– Adjuvant: eradication of micrometastases
– Concurrent: radiosensitization
• Disease stabilization
– new agents may lead to stability
• Chemoprevention
Goals of therapy
#1. Cure the patient
Established cancers reliably cured
by chemotherapy
– Testicular Cancer
– Lymphoma
– Choriocarcinoma
– Pediatric tumors
Goals of therapy
#2. Control the cancer
Cancers reliably shrunk by
chemotherapy (>50%)
– Small cell lung cancer
– Ovarian cancer
– Leukemia
– Nasopharyngeal cancer
– Hormonal therapy of prostate cancer
Goals of therapy
#2. Control the cancer
Cancers sometimes shrunk by
chemotherapy (30-50% responses)
– Non-small cell lung cancer
– Bladder cancer
– Breast cancer
– Colorectal cancer
– Stomach cancer
– Head and neck cancer
– Hormonal treatment of breast cancer
Goals of therapy
#2. Control the cancer
Cancers occasionally shrunk by
chemotherapy (5-20% responses)
– Pancreatic cancer
– Prostate cancer
– Cervical cancer
Goals of therapy
#2. Control the cancer
Cancers almost never shrunk by
chemotherapy(<5% responses)
–Kidney cancer
–Liver cancer
–Thyroid cancer
Palliative effects of chemotherapy
 Chemotherapy may shrink the tumor,
provide relief of symptoms and lead to
improvement

Chemotherapy may cause toxicity which
leads to deterioration
Benefits of tumor
growth delay
improvement
Toxicity of
therapy
deterioration
Pharmacology
• Pharmacokinetics
– “what the body does to the drug”…..
– absorption, distribution, metabolism and excretion
• Pharmacodynamics
– “what the drug does to the body”….
– e.g. nadir counts, non-hem toxicity, molecular
correlates
• Pharmacogenetics
– genetic differences in enzymatic metabolism or
receptor expression affecting patient outcome
Pharmacokinetics
• Absorption
– Bioavailability: proportion of orally administered
drug delivered into circulation.  if poor
absorption (e.g. gut problem) or high first-pass
metabolism
– Usually determined by measuring AUC
after oral vs iv adminstration
Conc
Time
Pharmacokinetics
• Distribution
dose
– Concentration = ________________
volume of distribution
– Distribution determined by:
• blood flow to tissues, permeability of tissue
membranes to drug
• protein binding to plasma proteins and tissue
components
• fat solubility
– Compartments: central (eg plasma),
peripheral
Pharmacokinetics
• Metabolism
– Most common site is liver
– Phase I (oxidative/reductive) reactions:
• eg Cytochrome P450 system cyclophosphamide, VP-16, vinca alkaloids
• eg Carboxylesterases - irinotecan
• eg DPD - 5-FU
• eg Cytosine deaminae - Ara-C
– Phase II (conjugative) reactions:
• eg Glucuronidation - SN-38, epirubicin
• eg N-acetylation; methyltransferases
Pharmacokinetics
• Excretion
– 2 major routes: renal and biliary
– Clearance: rate of elimination of drug from
the body = dose
AUC
– Half-life: time required for drug
concentration in plasma to  by half
• alpha -rate of distribution into tissues
• beta - rate of elimination from body
• gamma - in case of slow, delayed elimination
Pharmacodynamics
Pharmacodynamic
effects:
e.g. Toxicity,
Response (clinical,
biological,
molecular)
Pharmacokinetic
endpoints:
e.g. Dose, AUC,
Css (steady-state
concentration),
Time above a
threshold
concentration
Pharmacogenetics
• Differences in drug-metabolizing enzymes:
– e.g. DPD (dihydropyrimidine
dehydrogenase) in 5-FU metabolism
– e.g. Cytochrome P-450 enzymes e.g.
CYP3A4: cyclophosphamide (activation);
paclitaxel (inactivation)
• Differences in receptor expression:
– Less common
Conventional Chemotherapeutics
Drug Class
Mechanism(s) of Action
Examples
Alkylating
agents
 Alkylation of DNA
(generate +ve charge
intermediates which bind to
“nucleophilic” groups
Mustards
Nitrosoureas
Antimetabolites  Nucleoside (purines, pyrimidines)
analogues
 Antifolates (reduced folates)
 Inhibition of critical enzymes
necessary for DNA synthesis
TS inhibitors
Cytidine
analogues
MTX
Topoisomerase  Formation of “cleavable complex” Camptoinhibitors
thecins
with topoisomerase + DNA,
ultimately leading to DNA breaks Epidodophyllotoxins
Anthracyclines
Conventional Chemotherapeutics
Drug Class
Mechanism(s) of Action
Antimicrotubule  Disruption/Stabilization of mitotic
agents
spindle
 Pro-apoptotic (taxanes)
Examples
Vinca
alkaloids
Taxanes
Platinum
compounds
 Act like alkylators, produce
interstrand cross-links and
intrastrand adducts
Cisplatin
Carboplatin
Oxaliplatin
Antitumor
antibiotics
 Many are topoisomerase
inhibitors
 DNA intercalation
 Generation of oxygen radicals
 Bleomycin: causes DNA DSbreaks through binding of Bleoferrous iron complex to DNA
Anthracyclines
Bleomycin
Combination Chemotherapy
• Rationale:
– minimize resistance
– maximize synergy/additivity
– avoid drugs of overlapping toxicity
– cytokinetic considerations
– biochemical considerations
Combination Chemotherapy
• Rationale:
– biochemical considerations:
• addition of an agent to overcome drug
resistance (eg MDR inhibitor & vinca alkaloid)
• cooperative inhibition (eg leucovorin & 5FU)
• inhibition of drug breakdown (eg DPD inhibitor
& 5FU)
• rescue host from toxic effects of drug (eg
leucovorin following high-dose methotrexate)
Mechanisms of Drug Resistance
•  uptake into cells:
– eg methotrexate
•  efflux out of cells:
– eg vinca alkaloids; taxanes; anthracyclines
•  drug activation:
– eg many antimetabolites
•  drug catabolism:
– eg many antimetabolites
•  or  in target enzyme level:
– eg methotrexate (DHFR); 5FU (TS);
topoisomerase inhibitors
Mechanisms of Drug Resistance
• alterations in target enzyme:
– eg methotrexate; topoisomerase inhibitors
• inactivation by binding to sulfhydryls eg GSH:
– eg alkylating agents; cisplatin; anthracyclines
•  DNA repair:
– eg alkylating agents; cisplatin; anthracyclines;
etoposide
•  ability to undergo apoptosis:
– eg alkylating agents; cisplatin; anthracyclines;
etoposide
Stages of New Drug Development
Drug Discovery
Preclinical Evaluation
(In vitro/in vivo testing; toxicity;
pharmacology; formulation)
Phase I (dose and toxicity finding)
Phase II (efficacy testing)
Phase III (comparative)
Phase IV (post marketing)
Drug Discovery
• Strategies of new anticancer
drug discovery:
– Serendipitous observation
– Mass screening
– Analogue development
– Targeted drug synthesis
Phase I Clinical Trials
• First attempt at evaluating a novel drug or a
novel combination of existent drugs in
humans (volunteers or patients)
• Objectives:
– Determine maximum tolerated dose (MTD)
[= recommended phase II dose (RPTD)]
– Define toxicity profile
– Pharmacological evaluation
– Biological Correlation
– Collect preliminary evidence on antitumor
activity
Phase II Clinical Trials
• Primary endpoints:
“Response”: tumor shrinkage, marker
reduction
If tumor shrinkage is difficult to assess or not
expected (ie tumor stabilization is more likely),
then % of survival at n months, time-toprogression, etc. may be more relevant
– Time-defined endpoints (eg TTP) may be
difficult to apply because of lack of
comparators
Surrogate endpoints that have not been
externally validated are unacceptable as
primary endpoint
Phase III Clinical Trials
• Design and analysis:
– Controls: historical vs randomized controls
– Sample size: is the postulated difference
between experimental and control arms
realistic?
– Intention-to-treat principle: are all pts
accounted for?
– Endpoints: survival (median, overall,
progression-free), QoL
– Internal validity and external validity
cetuximab
trastuzumab
EGFR
HER-2
bevacizumab
VEGFR
PDGFR
Cell membrane
PF-00562271
FAK
dasatinib
AZD0530
erlotinib
gefinitib
SRC
lapatinib
sorafenib
lonafarnib
bosutinib
RAS
Nucleus
Farnesyl
transferase
PI3K
fRAS
perifosine
Cyclindependent
kinases
AKT
RAF
temsirolimus
RAD001
AP23573
mTOR
PHA-739358
MK-0457
MP 529
MLN 8054
AZD 1152
MEK
ERK
midostaurin
enzastaurin
Protein
kinase C
PROLIFERATION
26S
proteasome
flavopiridol
seliciclib
UCN-01
BMS-387082
vorinostat
Histone
deacetylases
Aurora
kinases
A, B, C
Bl 2356
HMN-214
PXD101
LBH589
FR901228
MS-275
Pololike
kinases
bortezomib
MIGRATION
METASTASES
ANGIOGENESIS