clinical pharmacology lillian siu. role of chemotherapy curative therapycurative therapy – ...
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Clinical PharmacologyClinical Pharmacology
Lillian SiuLillian Siu
Role of chemotherapyRole of chemotherapy• Curative therapyCurative therapy
survival survival
• Palliative therapyPalliative therapy quality of life, clinical benefitquality of life, clinical benefit
• Adjuvant therapyAdjuvant therapy– Neoadjuvant: downstagingNeoadjuvant: downstaging– Adjuvant: eradication of micrometastasesAdjuvant: eradication of micrometastases– Concurrent: radiosensitizationConcurrent: radiosensitization
• Disease stabilizationDisease stabilization– new agents may lead to stabilitynew agents may lead to stability
• Chemoprevention
Goals of therapyGoals of therapy
#1. Cure the patient#1. Cure the patientEstablished cancers reliably cured by Established cancers reliably cured by
chemotherapychemotherapy
– Testicular CancerTesticular Cancer– LymphomaLymphoma– ChoriocarcinomaChoriocarcinoma– Pediatric tumorsPediatric tumors
Goals of therapyGoals of therapy
#2.#2. Control the cancerControl the cancerCancers reliably shrunk by Cancers reliably shrunk by chemotherapy (>50%)chemotherapy (>50%)
– Small cell lung cancerSmall cell lung cancer– Ovarian cancerOvarian cancer– LeukemiaLeukemia– Nasopharyngeal cancerNasopharyngeal cancer– Hormonal therapy of prostate cancerHormonal therapy of prostate cancer
Goals of therapyGoals of therapy#2. Control the cancer#2. Control the cancerCancers sometimes shrunk by Cancers sometimes shrunk by
chemotherapy (30-50% responses)chemotherapy (30-50% responses)– Non-small cell lung cancerNon-small cell lung cancer– Bladder cancerBladder cancer– Breast cancerBreast cancer– Colorectal cancerColorectal cancer– Stomach cancerStomach cancer– Head and neck cancerHead and neck cancer– Hormonal treatment of breast cancerHormonal treatment of breast cancer
Goals of therapyGoals of therapy
#2.#2. Control the cancer Control the cancer Cancers occasionally shrunk by Cancers occasionally shrunk by
chemotherapy (5-20% responses)chemotherapy (5-20% responses)
– Pancreatic cancerPancreatic cancer– Prostate cancerProstate cancer– Cervical cancerCervical cancer
Goals of therapyGoals of therapy
#2.#2. Control the cancer Control the cancer Cancers almost never shrunk by Cancers almost never shrunk by
chemotherapy(<5% responses)chemotherapy(<5% responses)
–Kidney cancerKidney cancer–Liver cancerLiver cancer–Thyroid cancerThyroid cancer
Palliative effects of chemotherapyPalliative effects of chemotherapy Chemotherapy may shrink the tumor, Chemotherapy may shrink the tumor,
provide relief of symptoms and lead to provide relief of symptoms and lead to improvementimprovement
Chemotherapy may cause toxicity which Chemotherapy may cause toxicity which leads to deteriorationleads to deterioration
Benefits of tumor growth delay
Toxicity oftherapy
improvementimprovement deteriorationdeterioration
PharmacologyPharmacology
• PharmacokineticsPharmacokinetics – ““what the body does to the drug”…..what the body does to the drug”…..– absorption, distribution, metabolism and excretionabsorption, distribution, metabolism and excretion
• PharmacodynamicsPharmacodynamics– ““what the drug does to the body”….what the drug does to the body”….– e.g. nadir counts, non-hem toxicity, molecular correlatese.g. nadir counts, non-hem toxicity, molecular correlates
• PharmacogeneticsPharmacogenetics– genetic differences in enzymatic metabolism or receptor genetic differences in enzymatic metabolism or receptor
expression affecting patient outcomeexpression affecting patient outcome
PharmacokineticsPharmacokinetics
• AbsorptionAbsorption– Bioavailability:Bioavailability: proportion of orally administered proportion of orally administered
drug delivered into circulation. drug delivered into circulation. if poor absorption if poor absorption (e.g. gut problem) or high first-pass metabolism(e.g. gut problem) or high first-pass metabolism
– Usually determined by measuring AUC Usually determined by measuring AUC after oral vs iv adminstrationafter oral vs iv adminstration
ConcConc
TimeTime
PharmacokineticsPharmacokinetics
• DistributionDistribution– Concentration = ________________Concentration = ________________
– Distribution determined by:Distribution determined by:• blood flow to tissues, permeability of tissue blood flow to tissues, permeability of tissue
membranes to drugmembranes to drug• protein binding to plasma proteins and tissue protein binding to plasma proteins and tissue
componentscomponents• fat solubilityfat solubility
– Compartments: central (eg plasma), peripheralCompartments: central (eg plasma), peripheral
dosedosevolume of distributionvolume of distribution
PharmacokineticsPharmacokinetics• MetabolismMetabolism
– Most common site is Most common site is liverliver– Phase I (oxidative/reductive) reactions:Phase I (oxidative/reductive) reactions:
• eg Cytochrome P450 system - cyclophosphamide, VP-16, eg Cytochrome P450 system - cyclophosphamide, VP-16, vinca alkaloidsvinca alkaloids
• eg Carboxylesterases - irinotecaneg Carboxylesterases - irinotecan• eg DPD - 5-FUeg DPD - 5-FU• eg Cytosine deaminae - Ara-Ceg Cytosine deaminae - Ara-C
– Phase II (conjugative) reactions:Phase II (conjugative) reactions:• eg Glucuronidation - SN-38, epirubicineg Glucuronidation - SN-38, epirubicin• eg N-acetylation; methyltransferaseseg N-acetylation; methyltransferases
PharmacokineticsPharmacokinetics• ExcretionExcretion
– 2 major routes: renal and biliary2 major routes: renal and biliary– Clearance: Clearance: rate of elimination of drug from the body = rate of elimination of drug from the body =
dosedose
– Half-life: Half-life: time required for drug concentration in plasma time required for drug concentration in plasma to to by half by half• alphaalpha -rate of distribution into tissues -rate of distribution into tissues
• betabeta - rate of elimination from body - rate of elimination from body
• gammagamma - in case of slow, delayed elimination - in case of slow, delayed elimination
AUCAUC
PharmacodynamicsPharmacodynamics
Pharmacodynamic Pharmacodynamic effects:effects:
e.g. Toxicity, e.g. Toxicity, Response (clinical, Response (clinical, biological, biological, molecular)molecular)
Pharmacokinetic Pharmacokinetic endpoints:endpoints:
e.g. Dose, AUC, e.g. Dose, AUC, Css (steady-state Css (steady-state concentration), concentration), Time above a Time above a threshold threshold concentrationconcentration
PharmacogeneticsPharmacogenetics
• Differences in drug-metabolizing enzymes:Differences in drug-metabolizing enzymes:
– e.g. DPD (dihydropyrimidine e.g. DPD (dihydropyrimidine dehydrogenase) in 5-FU metabolismdehydrogenase) in 5-FU metabolism
– e.g. Cytochrome P-450 enzymes e.g. e.g. Cytochrome P-450 enzymes e.g. CYP3A4: cyclophosphamide (activation); CYP3A4: cyclophosphamide (activation); paclitaxel (inactivation)paclitaxel (inactivation)
• Differences in receptor expression:Differences in receptor expression:
– Less commonLess common
Conventional ChemotherapeuticsConventional ChemotherapeuticsDrug Class Mechanism(s) of Action Examples
Alkylatingagents
Alkylation of DNA (generate +ve charge
intermediates which bind to“nucleophilic” groups
MustardsNitrosoureas
Antimetabolites Nucleoside (purines, pyrimidines)analogues
Antifolates ( reduced folates) Inhibition of critical enzymes
necessary for DNA synthesis
TS inhibitorsCytidineanaloguesMTX
Topoisomeraseinhibitors
Formation of “cleavable complex”with topoisomerase + DNA,ultimately leading to DNA breaks
Campto-thecinsEpidodo-phyllotoxinsAnthra-cyclines
Conventional ChemotherapeuticsConventional Chemotherapeutics
Drug Class Mechanism(s) of Action Examples
Antimicrotubuleagents
Disruption/Stabilization of mitoticspindle
Pro-apoptotic (taxanes)
VincaalkaloidsTaxanes
Platinumcompounds
Act like alkylators, produceinterstrand cross-links andintrastrand adducts
CisplatinCarboplatinOxaliplatin
Antitumorantibiotics
Many are topoisomeraseinhibitors
DNA intercalation Generation of oxygen radicals Bleomycin: causes DNA DS-
breaks through binding of Bleo-ferrous iron complex to DNA
Anthra-cyclinesBleomycin
Combination ChemotherapyCombination Chemotherapy
• Rationale:Rationale:– minimize resistanceminimize resistance
– maximize synergy/additivitymaximize synergy/additivity
– avoid drugs of overlapping toxicityavoid drugs of overlapping toxicity
– cytokinetic considerationscytokinetic considerations
– biochemical considerationsbiochemical considerations
Combination ChemotherapyCombination Chemotherapy
• Rationale:Rationale:– biochemical considerations:biochemical considerations:
• addition of an agent to overcome drug addition of an agent to overcome drug resistance (eg MDR inhibitor & vinca alkaloid)resistance (eg MDR inhibitor & vinca alkaloid)
• cooperative inhibition (eg leucovorin & 5FU)cooperative inhibition (eg leucovorin & 5FU)• inhibition of drug breakdown (eg DPD inhibitor inhibition of drug breakdown (eg DPD inhibitor
& 5FU)& 5FU)• rescue host from toxic effects of drug (eg rescue host from toxic effects of drug (eg
leucovorin following high-dose methotrexate)leucovorin following high-dose methotrexate)
Mechanisms of Drug ResistanceMechanisms of Drug Resistance uptake into cells:uptake into cells:
– eg methotrexateeg methotrexate
efflux out of cells:efflux out of cells:– eg vinca alkaloids; taxanes; anthracyclineseg vinca alkaloids; taxanes; anthracyclines
drug activation:drug activation:– eg many antimetaboliteseg many antimetabolites
drug catabolism:drug catabolism:– eg many antimetaboliteseg many antimetabolites
or or in target enzyme level: in target enzyme level:– eg methotrexate (DHFR); 5FU (TS); topoisomerase eg methotrexate (DHFR); 5FU (TS); topoisomerase
inhibitorsinhibitors
Mechanisms of Drug ResistanceMechanisms of Drug Resistance
• alterations in target enzyme:alterations in target enzyme:– eg methotrexate; topoisomerase inhibitorseg methotrexate; topoisomerase inhibitors
• inactivation by binding to sulfhydryls eg GSH:inactivation by binding to sulfhydryls eg GSH:– eg alkylating agents; cisplatin; anthracyclineseg alkylating agents; cisplatin; anthracyclines
DNA repair:DNA repair:– eg alkylating agents; cisplatin; anthracyclines; eg alkylating agents; cisplatin; anthracyclines;
etoposideetoposide
ability to undergo apoptosis:ability to undergo apoptosis:– eg alkylating agents; cisplatin; anthracyclines; eg alkylating agents; cisplatin; anthracyclines;
etoposideetoposide
Stages of New Drug DevelopmentStages of New Drug Development
Drug DiscoveryDrug Discovery
Preclinical EvaluationPreclinical Evaluation
(In vitro/in vivo testing; toxicity; (In vitro/in vivo testing; toxicity;
pharmacology; formulation)pharmacology; formulation)
Phase IPhase I (dose and toxicity finding) (dose and toxicity finding)
Phase IIPhase II (efficacy testing) (efficacy testing)
Phase IIIPhase III (comparative) (comparative)
Phase IVPhase IV (post marketing) (post marketing)
Drug DiscoveryDrug Discovery
• Strategies of new anticancer Strategies of new anticancer drug discovery:drug discovery:
– Serendipitous observationSerendipitous observation
– Mass screeningMass screening
– Analogue developmentAnalogue development
– Targeted drug synthesisTargeted drug synthesis
Phase I Clinical TrialsPhase I Clinical Trials
• First attempt at evaluating a novel drug or a novel First attempt at evaluating a novel drug or a novel combination of existent drugs in humans combination of existent drugs in humans (volunteers or patients)(volunteers or patients)
• Objectives:Objectives:– Determine maximum tolerated dose (MTD) [= Determine maximum tolerated dose (MTD) [=
recommended phase II dose (RPTD)]recommended phase II dose (RPTD)]
– Define toxicity profileDefine toxicity profile
– Pharmacological evaluationPharmacological evaluation
– Biological CorrelationBiological Correlation
– Collect preliminary evidence on antitumor activityCollect preliminary evidence on antitumor activity
Phase II Clinical TrialsPhase II Clinical Trials• Primary endpoints:Primary endpoints:
““Response”: tumor shrinkage, marker Response”: tumor shrinkage, marker reductionreduction
If tumor shrinkage is difficult to assess or not If tumor shrinkage is difficult to assess or not expected (ie tumor stabilization is more likely), expected (ie tumor stabilization is more likely), then % of survival at n months, time-to-then % of survival at n months, time-to-progression, etc. may be more relevantprogression, etc. may be more relevant
– Time-defined endpoints (eg TTP) may be Time-defined endpoints (eg TTP) may be difficult to apply because of lack of difficult to apply because of lack of comparatorscomparators
Surrogate endpoints that have not been Surrogate endpoints that have not been externally validated are unacceptable as externally validated are unacceptable as primary endpointprimary endpoint
Phase III Clinical TrialsPhase III Clinical Trials• Design and analysis:Design and analysis:
– Controls: historical vs randomized controlsControls: historical vs randomized controls– Sample size: is the postulated difference Sample size: is the postulated difference
between experimental and control arms between experimental and control arms realistic?realistic?
– Intention-to-treat principle: are all pts Intention-to-treat principle: are all pts accounted for?accounted for?
– Endpoints: survival (median, overall, Endpoints: survival (median, overall, progression-free), QoLprogression-free), QoL
– Internal validity and external validityInternal validity and external validity
EGFR VEGFR PDGFRHER-2
Cell membrane
lapatinib
cetuximab
erlotinibgefinitib
sorafenib
trastuzumab bevacizumab
ANGIOGENESIS
PHA-739358MK-0457
MP 529MLN 8054AZD 1152
bortezomib
temsirolimusRAD001
AP23573
perifosine
Aurora kinases A, B, C
Nucleus
PROLIFERATION MIGRATION METASTASES
PI3K
AKT
mTOR
26S proteasome
RAS
RAF
Farnesyltransferase
lonafarnibSRC
dasatinibAZD0530
bosutinib
FAKPF-00562271
Cyclin-dependent
kinases
flavopiridolseliciclibUCN-01BMS-387082
Polo-like
kinases
Bl 2356HMN-214
Protein kinase C
midostaurinenzastaurin
Histone deacetylases
vorinostatPXD101LBH589FR901228MS-275
MEK
fRAS
ERK