Lecture anticancer agents

7/25/2019 Lecture anticancer agents

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Therapeutic PrinciplesTherapeutic Principles

Diagnosis

&Drug

Selection

I

N

P

U

T

Absorption

DistributionMetabolism

Elimination

Toxicity

&/OR

Eicacy

P!armaco"inetics P!armaco#ynamics


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Therapeutic EndpointsTherapeutic Endpoints

Efficacy ithout to!icityEfficacy ithout to!icity "uman medicine# palliati$e therapy only"uman medicine# palliati$e therapy only %eterinary medicine# palliati$e therapy pro&a&ly'%eterinary medicine# palliati$e therapy pro&a&ly'

Efficacy A(D to!icityEfficacy A(D to!icity "uman and $eterinary medicine# aggressi$e) curati$e therapy"uman and $eterinary medicine# aggressi$e) curati$e therapy

To!icity ithout efficacyTo!icity ithout efficacy Tentati$e administrationTentati$e administration

*ou may affect &one marro +(,* rather than &one marro A(D*ou may affect &one marro +(,* rather than &one marro A(Dtumortumor

Drug ResistanceDrug Resistance

Reduces tumor response) &one marro still sensiti$eReduces tumor response) &one marro still sensiti$e

(either to!icity nor efficacy(either to!icity nor efficacy


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Dosing $. Pkinetic End PointsDosing $. Pkinetic End Points

ET"ERET"ER mg/kg 0/1mg/kg 0/1223 4 inter$al 4 duration3 4 inter$al 4 duration

+R+R Peak drug concentration) A5CPeak drug concentration) A5C

0Concentration 4 Time3) Time a&o$e0Concentration 4 Time3) Time a&o$etarget concentration) Cumulati$e dose)target concentration) Cumulati$e dose)

Cumulati$e A5CCumulati$e A5C W"C" one depends on drug.W"C" one depends on drug.

6ase choice on clinical trials76ase choice on clinical trials7


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Dose $s A5C TargetDose $s A5C Target

Nagahiro Saijo, Chemotherapy# the more the &etter' +$er$ie) $ancer $!emot!er P!armacol '(()* +,

Suppl*- S',,. S',

These are the 8A1E PATE(T8. What separates them on the 9raph la&eled

:A; '


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Peak ConcentrationPeak Concentration


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A5CA5C


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A&sorptionA&sorption

+ral+ral %aria&le concentration 4 time profile%aria&le concentration 4 time profile

Typical factors affecting oral a&sorptionTypical factors affecting oral a&sorption

Presence of foodPresence of food

Concurrent diseaseConcurrent disease

,ikely produces a different efficacy / to!icity,ikely produces a different efficacy / to!icity

profileprofile


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A&sorptionA&sorption

ntramuscularntramuscular %ER* fe anti-cancer drugs can &e gi$en this%ER* fe anti-cancer drugs can &e gi$en this

ayay

Cytoto!icity associated ith tissue damage atCytoto!icity associated ith tissue damage at

in


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Acti$ationActi$ation

"epatic"epatic e.g. cyclophosphamide) do!oru&icin)e.g. cyclophosphamide) do!oru&icin)

daunoru&icin) othersdaunoru&icin) others

ntracellular phosphorylationntracellular phosphorylation e.g fludara&inee.g fludara&ine

Tissue meta&olism ith free radicalTissue meta&olism ith free radical

productionproduction e.g. do!oru&icine.g. do!oru&icin


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Distri&utionDistri&ution

1ost target intra-cellular sites1ost target intra-cellular sites Com&ination solu&ility 0ater#lipid3Com&ination solu&ility 0ater#lipid3

%ery fe penetrate &lood-&rain &arrier%ery fe penetrate &lood-&rain &arrier

Protein &indingProtein &inding "igh protein &inding increases interaction"igh protein &inding increases interaction

potentialpotential

1ay or may not limit tissue :penetration;1ay or may not limit tissue :penetration;Consider &oth plasma and tissue proteinsConsider &oth plasma and tissue proteins


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Distri&utionDistri&ution

Acti$e 1eta&olite distri&utionActi$e 1eta&olite distri&ution fosfamide meta&olites cross &lood-&rain &arrierfosfamide meta&olites cross &lood-&rain &arrier

Consider local factorsConsider local factors Tumor $ascularityTumor $ascularity

Tumor may outgro &lood supplyTumor may outgro &lood supply

nteraction ith angiogenesis inhi&itors'nteraction ith angiogenesis inhi&itors'

P-glycoprotein cell mem&rane pumpP-glycoprotein cell mem&rane pumpdrug efflu! pump = 0something like anti&ioticdrug efflu! pump = 0something like anti&iotic

resistance &y &acteria3resistance &y &acteria3


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EliminationElimination

"epatic 1eta&olism"epatic 1eta&olism P>?@ meta&olismP>?@ meta&olism

Cata&olism 0especially anti-meta&olites3Cata&olism 0especially anti-meta&olites3 (ormal degradation pathays for amino acids(ormal degradation pathays for amino acids

etc. to car&on dio!ide and ateretc. to car&on dio!ide and ater

"ydrolysis"ydrolysis

Renal elimination unchanged 0hat doesRenal elimination unchanged 0hat does

this mean for oner safety'3this mean for oner safety'3


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Dosing ChemotherapeuticsDosing Chemotherapeutics

What are e really doing in $eterinaryWhat are e really doing in $eterinarypatients'patients' Critiuing dose regimes ith more emphasisCritiuing dose regimes ith more emphasis

on to!icity than efficacyon to!icity than efficacy8o ere dosing for palliation in most cases'8o ere dosing for palliation in most cases'

8pecifics of the approach to dosing &ecome8pecifics of the approach to dosing &ecomemore important as the therapy &ecomes moremore important as the therapy &ecomes more

aggressi$e.aggressi$e. We should formulateWe should formulate clear and specificclear and specific

therapeutic goalstherapeutic goals


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6ody surface area6ody surface area

mg/kgmg/kg

Total doseTotal doseDose to pharmacokinetic targetDose to pharmacokinetic target A5C) Peak) etc.A5C) Peak) etc.

Therapeutic monitoring la&oratory capa&ilityTherapeutic monitoring la&oratory capa&ilityreuired.reuired.


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Traditional dosing on 6ody 8urface AreaTraditional dosing on 6ody 8urface Area Correlates ith meta&olic rate) $olume ofCorrelates ith meta&olic rate) $olume of

distri&utiondistri&ution

Correlation ith tissue concentrations'Correlation ith tissue concentrations'Efficacy and to!icityEfficacy and to!icity

E!trapolated 0ith enthusiasm from humanE!trapolated 0ith enthusiasm from humandose recommendations3dose recommendations3

Pro&a&ly correct for 8+1E &ut not A,,Pro&a&ly correct for 8+1E &ut not A,,protocolsprotocols


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6ody 8urface Area6ody 8urface Area

DogsDogs

CatsCats

These are appro!imations.These are appro!imations. 1an/Woman = ? formulas) all include height) some1an/Woman = ? formulas) all include height) some

gender) some ageBgender) some ageB

( ) 0/1

,,,2',gramsin', bw

( ) 0/1

,,,2',

gramsin'3', bw


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1eters8Auare

d


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Arrington et al. AJ%R ??03 ?-F2Arrington et al. AJ%R ??03 ?-F2 G@ mg/1G@ mg/122AdriamycinAdriamycin

Dogs H@ kg recei$ed more than .? mg/kgDogs H@ kg recei$ed more than .? mg/kg

ncreased incidence of to!icityncreased incidence of to!icity

Dogs I@ kg recei$ed less than .@ mg/kgDogs I@ kg recei$ed less than .@ mg/kg

8tudy did not e$aluate differential efficacy8tudy did not e$aluate differential efficacy

Potential for &reed-related differences in to!icityPotential for &reed-related differences in to!icity

This sort of study -IThis sort of study -I

alter 68A formulas'alter 68A formulas'

8itch to mg/kg dosing'8itch to mg/kg dosing'


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+ral Chemotherapy+ral Chemotherapy

Widely used in %eterinary ChemotherapyWidely used in %eterinary Chemotherapy Concerns for patient :discomfort;Concerns for patient :discomfort;

nfreuent use of :indelling; linesnfreuent use of :indelling; lines

Palliation is primary goalPalliation is primary goal

"igh peak concentrations or large A5C are not a"igh peak concentrations or large A5C are not a

concernconcern

Dosing control is not as criticalDosing control is not as critical


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Alkylating AgentsAlkylating Agents cyclophosphamide 0Cyto!an3cyclophosphamide 0Cyto!an3

E!cellent a&sorption characteristicsE!cellent a&sorption characteristics

1ost idely used 0therefore most e!perience31ost idely used 0therefore most e!perience3

+ncology) immunology uses+ncology) immunology uses

melphalon 0Alkeran3melphalon 0Alkeran3

&usolfan 01yleran3&usolfan 01yleran3 procar&aine 01utalane3procar&aine 01utalane3


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Antimeta&olitesAntimeta&olites capecita&ine 04eloda3capecita&ine 04eloda3

+ral pro-drug $ersion of fluorouracil+ral pro-drug $ersion of fluorouracil

1ercaptopurine 0Purinethiol31ercaptopurine 0Purinethiol3

%aria&le and incomplete a&sorption%aria&le and incomplete a&sorption


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"ormonal +ncologics"ormonal +ncologics Tamo!ifenTamo!ifen

1itosis nhi&itors1itosis nhi&itors Etoposide 0%PK) %epesed3Etoposide 0%PK) %epesed3

%aria&le dose-dependent oral &ioa$aila&ility%aria&le dose-dependent oral &ioa$aila&ility

+thers+thers

"ydro!urea"ydro!ureaWell a&or&edWell a&or&ed


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1 Chemotherapy1 Chemotherapy

aspariginase 0Elspar3aspariginase 0Elspar3 1 is thought to produce feer allergic1 is thought to produce feer allergic

reactionsreactions

(ot confirmed ith large num&er of cases(ot confirmed ith large num&er of cases

leuprolide 0,upron3leuprolide 0,upron3 8hort acting 9nR" Agonist8hort acting 9nR" Agonist


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ntra$enous Chemotherapyntra$enous Chemotherapy

Why'Why' Drugs) and sometimes $ehicles) too irritatingDrugs) and sometimes $ehicles) too irritating

0cytoto!ic3 &y other routes0cytoto!ic3 &y other routes

Produce high peak concentrationProduce high peak concentration

+PP+RT5(T* to e!ert e!treme control o$er+PP+RT5(T* to e!ert e!treme control o$er

plasma concentrations.plasma concentrations.


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9emcita&ine9emcita&ine

Controlled intra$enous infusionControlled intra$enous infusion 1eta&olism to acti$e compounds may &e1eta&olism to acti$e compounds may &e

satura&lesatura&le

Rates of administration that saturate con$ersionRates of administration that saturate con$ersionrate aste drugrate aste drug

e.g.) 5n-con$erted gemcita&ine is eliminated in the urine.e.g.) 5n-con$erted gemcita&ine is eliminated in the urine.

Rates of administration e!ceeding con$ersionRates of administration e!ceeding con$ersion

produce less acti$ity per milligram of drug.produce less acti$ity per milligram of drug.@ mg gi$en sloly -I L@ mg of acti$ity@ mg gi$en sloly -I L@ mg of acti$ity

@ mg gi$en rapidly -I L mg of acti$ity@ mg gi$en rapidly -I L mg of acti$ity


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Dose Morm 1anipulationDose Morm 1anipulation

,iposomes,iposomes Drug contained in lipid spheresDrug contained in lipid spheres

Essentially artificial liposomal mem&ranesEssentially artificial liposomal mem&ranes

Acti$ely acuired &y some cell linesActi$ely acuired &y some cell lines

mpro$ed therapeutic inde!mpro$ed therapeutic inde!

Reduced cardioto!icityReduced cardioto!icity

Enhanced acti$ityEnhanced acti$ity0although certain other to!icities may &e0although certain other to!icities may &e

enhanced3enhanced3


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Dose Morm 1anipulationDose Morm 1anipulation

Chemoem&oliationChemoem&oliation Arterial infusion of methylcellulose micro-Arterial infusion of methylcellulose micro-

capsules filled ith chemotherapeuticscapsules filled ith chemotherapeutics

mplanta&le polymersmplanta&le polymers 8urgical implantation of &iodegrada&le8urgical implantation of &iodegrada&le

polymers containing chemotherapeuticspolymers containing chemotherapeutics

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Lecture anticancer agents