Clinical Pharmacology
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Transcript Clinical Pharmacology
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