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Pharmacokinetic and Pharmacodynamic Considerations in Cancer Chemotherapy
Indications and Dosing
Daniel L. Gustafson, PhDProfessorShipley University Chair in Comparative OncologyColorado State University
Outline of Discussion• Pharmacokinetics
• Parameters• Variability
• Pharmacodynamics• Toxicity• Efficacy• Surrogate Measures of Response
• Dose Normalization• Per kg, per m2
• Other dosing metrics
• Drug Dosing of Specific Agents• Dose finding studies• Selecting the proper dose, dose interval and what to measure
Pharmacokinetics (PK) and Pharmacodynamics (PD)How are they related?
Dose PharmacokineticsDrug
Levels at Target
Pharmacodynamics ResponseGeneticsBody SizeEnvironmentPhysiologyDiet
GeneticsEnvironmentPhysiologyDiet
Through Drug Exposure at the Site of Action
Blood
PharmacokineticsChemotherapy Drug ResponseThe pharmacokinetic parameters of a given drug are important because they are the link between doseand response as they represent a measure of drug exposure.
Common Assumptions of Drug Therapy• Dose is related to drug exposure– Higher dose leads to proportional increase in drug exposure
• Drug exposure is related to response– An increase in drug exposure will increase drug response, both good and bad
• Blood/serum/plasma drug levels are a good indicator of drug exposure– Circulating levels of drug in the blood are proportional to “target tissue” drug levels
Dose PK⎯ →⎯ Exposure PD⎯ →⎯ Response
PharmacokineticsIs Dose Proportional to Exposure?
In general, drug exposure is proportional to dose. However,notice the variability in exposure across the population. Dose PK⎯ →⎯ Exposure PD⎯ →⎯ Response
PLoS One 5:e11013, 2010
Pharmacokinetics• The fate of a therapeutic agent when administered to a living organism• Commonly described by drug levels measured in the blood compartment
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Time (hr)
[Dox
orub
icin
] seru
m (n
M)
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Time (hr)
[Dox
orub
icin
] seru
m (n
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Data from 28 dogs treated with Doxorubicin @30mg/m2 via a 20 minute infusion
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PharmacokineticsIV bolus/short infusion administration of infrequent doses
• Measured Parameters• Cmax – maximal concentration achieved• AUC – drug exposure as determined by concentration x time• Terminal Half-Life – how long it takes drug to decay in the blood
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Time (hr)
[Dox
orub
icin
] seru
m (n
M) Cmax
AUC (Area Under the Curve)
Terminal half-life (t1/2)
PharmacokineticsMultiple-Doses Given Frequently
• Measured Parameters• Cmax
• Tmax – time to reach Cmax
• Terminal half-life – plays a role in dosing interval and accumulation• Cmin – also referred to as trough
• Cmax is a function of dose, t1/2
and Tau• Cmin is a function of dose, t1/2
and Tau• Cavg is a function of dose, t1/2
and Tau• Accumulation factor is
dependent on t1/2 and Tau• Tmax is dependent kabs and t1/2
How can Cavg be the same but Cmin and Cmax be different?
PharmacokineticsPro-Drugs
• Many clinically-used anti-tumor agents are actually pro-drugs and need to be activated in one way or another.
What should you actually measure?
PharmacokineticsPro-Drugs
0 1 2 3 4 5 61
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Time (hr)
[Cyc
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osph
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/ml)
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IV DosingOral Dosing
Time (hr)
[4-O
H-C
P] p
lasm
a (ng
/ml)
Dogs receiving 250 mg/m2 cyclophosphamide either IV or PO
Measuring the active drug isvery important in this case. Ifyou just measured the CP itwould seem that you wereunderdosing via the PO routeand would suggest doseescalating. The 4-OH-CP datatells a completely differentstory.
PharmacokineticsCyclophosphamide PK in Cats
0 60 120 180 240 300 360 420 4801
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Time (min)
[Cyc
loph
osph
amid
e] pl
asm
a (ng
/ml)
Cyclophosphamide
IVIPPO
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[4-O
HC
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asm
a (ng
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4-OH CP
IVIPPO
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AU
C/D
ose
IVIPPO
Cyclophosphamide 4-OH-CP
PK of CP and 4-OHCP is similar in cats as 4-OHCP exposure is similar via the IV or PO route
PharmacokineticsVariability – Doxorubicin Exposure
0 2 4 610
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Time (hr)
[Dox
orub
icin
] seru
m n
g/m
l
AUC0-6hr
Mean = 455 ng/ml�hrMinimum = 332 ng/ml�hrMaximum = 697 ng/ml�hr
Doxorubicin dosed at 30 mg/m2 in dogs shows an exposure range in 20 dogs that can vary by ~2X. In this cohort, there was no measured variable that could account for any of the variability.
Where does the variability come from?- For doxorubicin this is a bit unclear- Inter-patient variability (CV%) ~ 24%- Intra-patient variability (CV%) ~ 18%
Dose 1 Dose 20
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C (n
g/m
l x m
in)
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PharmacokineticsVariability – Doxorubicin Exposure
No covariates were defined in arecent Pop-PK analysis in humansalthough DOX and DOXol exposurecorrelated with hematologicaltoxicity…. We’ll get back to this later.
What does this mean?
• Adjusting DOX dosing based on renal orhepatic function has not been established
• DOX metabolism to DOXol does not correlatein any meaningful way with exposure but thecombination of DOX + DOXol may be moreinformative than just DOX
• DOX exposure is related to dose but highintra-patient variability makes doseadjustment difficult within a patient
25 mg/m2 30 mg/m20
1020304050
500600700800900
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Doxorubicin Dose
DO
X Ex
posu
re se
rum
AUC0-6h
AUC/Dose
*P=0.016
PharmacokineticsVariability - Vinblastine
0 30 60 90 120
150
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960
1440
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1000
Minutes
Vinb
last
ine s
erum
(ng/
mL)
Variability in exposure (AUC) showed a CV (%) of 60.5 and varied from 3,091 ng/ml�min to 20,743 ng/ml�min.
PK Parameters following a dose of 2.5 mg/m2
IV bolus dose of vinblastine sulfate in dogs
PharmacokineticsVariability - Vinblastine
Consequences of high variability
0
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Vin
blas
tine
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osur
e Toxicity
Efficacy with Acceptable Toxicity
Sub-therapeuticDose PK⎯ →⎯ Exposure PD⎯ →⎯ Response
• Higher fractions of patients fall into exposureranges that may result in less than optimalresponses and more serious toxicities
• More complex dosing metrics are neededthat attempt to reduce variability
• Without knowledge of inter- vs. intra-patientvariability, dose escalation or reductionwithin a patient is difficult to interpret.
NOTE: The values shownhere for toxicity and sub-therapeutic are made upand only for illustration
Dose-Exposure-Response
Dose Blood
Tissues
Tumor
PK
PDToxicity
PDEfficacy
Response These things are related
Drug effect is related to drug exposure… even for oncology.
PharmacokineticsIs Dose Related to Response?
3.0 3.5 40
20
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60
0/3
4/16
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Vinblastine Dose (mg/m2)
% w
ith G
rade
III/I
V N
eutr
open
ia This Phase I data from a study of single agentvinblastine in dogs provides some evidence that doseis related to toxic response (neutropenia). However,without any data with regards to exposure the powerto compare within and between groups and to add agraded component to the dosing groups is lost.
In oncology this is a tough one… Dosing and drug exposure is usually limited to not elicit atoxic response, which is presumably related to therapeutic response. In general, it isassumed that dose intensity will correlate with response.
Dose PK⎯ →⎯ Exposure PD⎯ →⎯ Response
PharmacokineticsIs exposure related to response?
Drug exposure is related to response in the most direct manner and as such being able topredict drug exposure from a given dose would be the most exact way to have a moreuniform dose-response relationship across a population.
This study in humans shows a clearrelationship between exposure tovinblastine and the % decrease inabsolute neutrophil count at thenadir within the cycle.
Dose PK⎯ →⎯ Exposure PD⎯ →⎯ Response
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% R
edu
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Relationships Between Drug Exposure and PD ResponseVinblastine PK/PD in Dogs
Nice clear relationship with exposure and neutropenia… All right!!!
025
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edu
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tro
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ils
Until you include all the data.. Which shows no relationshipbetween exposure as measured by AUC and neutropenia.This may be due to sampling at the wrong time.
Toxicity and Response to Chemotherapy
Grade III and IV NeutropeniaNeutrophils < 3000/μl
Multiple studies have shown that dogs that have side effects associated with chemotherapy have better outcomes with regards to length of remission and survival time in lymphoma
PharmacodynamicsToxicity as an Endpoint
https://www.cancer.gov/about-cancer/treatment/clinical-trials/what-are-trials/phases
In human cancer drug development, toxicity is an endpoint that is defined in Phase I trials. The majority ofchemotherapy drugs used in veterinary medicine have not undergone controlled clinical trials or what arecommonly referred to as “Registration Trials” to define the indication of a specific drug. The off-label use ofthese drugs means that the doses commonly used are based on a compilation of information from thecombined experience of the veterinary oncology community.
PharmacokineticsDo we even need PK?
Dose PK⎯ →⎯ Exposure PD⎯ →⎯ Response
In oncology, generally the toxic effect of the drug is related to the therapeutic activity so if you dose to a“Response-metric” associated with toxicity you can potentially get a prediction of response. The problem is thatthis requires assessment of response and includes a delay in dose adjustment
This argues that:1. Toxicity and efficacy are interrelated
a) Presumably by exposure2. Dose to toxicity3. Response is the only metric you need
Pharmacokinetic/Pharmacodynamic RelationshipDose PK⎯ →⎯ Exposure PD⎯ →⎯ Response
What do we need to make the best prediction within a patient with regards to dose-response?
1. PK data/modeling to predict exposure from a given dose to an individual• Data-based models that rely on sampling• Correlations between dose-exposure and patient characteristics (PopPK)
2. PD data/modeling to predict response from drug exposure to an individual• Data-based models that rely on sampling• Known relationships between exposure and response based on known patient
characteristics
What does this look like? Let’s tell a story with doxorubicin
Limited Sampling Model to Predict DOX ExposureCalculate exposure without full time course sampling
500 1000 1500500
1000
1500r2=0.919
Measured AUC0→6hr (nM•hr)
Pred
icte
d A
UC
0→6h
r (nM
•hr)
𝐴𝑈𝐶$→&'( 𝑛𝑀 + ℎ𝑟 = 46.9 + 0.63 𝐶6789 + 1.96 𝐶;6789 + 6.63(𝐶&$789)
This allows for drug exposure data to becalculated with only 3 samples being collectedwithin the first hour of treatment. This leads toan increase in compliance as patients need onlybe in the clinic for an hour after the end of druginfusion for all samples to be collected. Muchbetter than having a full time course of samplescollected over 6 hours.
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PK/PD RelationshipsHematologic Toxicity of DOX• Using the limited sampling approach for DOX prediction of exposure (AUC), 44 dogs were
enrolled in a trial looking at DOX AUC and hematologic toxicity
DOX exposure negatively correlated with WBC and neutrophil count
Exposure – PD RelationshipHematologic Toxicity of DOX
Using the information that DOX AUC and baseline neutrophil count are significantlycorrelated with the degree of neutropenia, a model was developed to predict the ANCat nadir based on these values
Dose PK⎯ →⎯ Exposure PD⎯ →⎯ Response
PK/PD RelationshipsHematologic Toxicity of DOX
𝑁𝑎𝑑𝑖𝑟 𝐴𝑁𝐶 = 0.816 + 0.603 + 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝐴𝑁𝐶 − (0.002 + 𝐷𝑂𝑋 𝐴𝑈𝐶)
We can predict neutropenia based on baseline ANC andDOX exposure monitored using a limited samplingapproach that only requires 3 PK samples taken duringthe first hour post drug infusion
What does this potentially allow you to do?
Neutrophils < 3000/μl
1. Treat with DOX at a standard dose (30 mg/m2)2. Collect 3 PK samples within the first-hour• Have samples measured for DOX• Calculate out AUC
3. Calculate out expected ANC at nadir4. Adjust dose to target ANC at nadir based on
DOX exposure and baseline ANC
Based on the relationship between neutropenia following therapy and length of first-remission shown in multiple studies, this type of approach should lead to better outcomes…. Of course a prospective trial with some type of dose adaptation is the ideal way to test this.
Should you be pleased when a patient shows no adverse effect(s) from a cycle of chemotherapy?
Let’s take a 10 minute break Dosing Calculations and MetricsOr…. Where the heck do these doses come from and why do we dose based on surface area
1. Body surface area (BSA) dosing is based on the assumption that drug clearance correlates with BSA
2. There is an assumption that individuals of different sizes should be given different doses
3. The calculations used for estimating BSA in both humans and animals are based on very small sample sizes and have highly questionable accuracy in relating weight and height/length to a measure of BSA
4. Studies in humans have effectively shown that BSA dosing cannot account for an appreciable amount of variability in PK.
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Goal of Dose NormalizationTo minimize interindividual variation, dosing for most anti-cancer agents are normalized as mg per m2 of body surface area. This is referred to as BSA-based dosing.
Drug Exposure (AUC)Frac
tion
of In
divi
dual
s Tr
eate
d w
ith D
rug
X
Fixed-Dose (i.e. 100 mg)
Normalized-Dose (i.e. 200 mg/m2)
Dose PK⎯ →⎯ Exposure PD⎯ →⎯ Response
Body surface area (BSA) dosing is based on the assumption that drug clearance correlates with BSA
• Cardiac output correlates with BSA• GFR does not correlate well with BSA• Liver volume correlates with BSA
Drug clearance is a function of both drug distribution and rate of elimination. Thus, there are components of drug clearance that should relate to BSA…. But…. there are components that BSA has no relation to
There is an assumption that individuals of different sizes should be given different doses
This is more important in veterinary medicine…. Why?
Human range in height may be 20% when looking ataverages within groups…. Weight is probably a bitwider due to variability in body shape.
The variability from theSmall to the X-Largegroup is 350%-600% andthis is excluding the twoextremes (X-Small andXX-Large)…. It is fair toassume that a dachshundand a rottweiler shouldget different doses….Even though they mighthave the same colorings.
The calculations used for estimating BSA in both humans and animals are based on very small sample sizes and have highly questionable accuracy in relating weight and height/length to a measure of BSA
Most commonly, BSA is calculated using the DuBois and DuBois equation:
• Arch Internal Med 17:863-871, 1916• Based on measurements made on 9 patients in the early 1900’s
Humans
𝐵𝑆𝐴 = 0.007184 + 𝑤𝑒𝑖𝑔ℎ𝑡$.;R6 + ℎ𝑒𝑖𝑔ℎ𝑡$.SR6
But, more than 25 BSA formulae exist and they can give wildly different measures…..
Veterinary MedicineEquations used are not based on large studies and which equation is used can lead to disparate calculations of dose. Further, the calculation is only based on weight and does not take into account other variables in size.
Studies in humans have effectively shown that BSA dosing cannot account for an appreciable amount of variability in PK
Plenty of data from human trialsshowing that fixed dosing may be asgood or better than BSA dosing inhumans.
There are some major differences inVet Med…. but.. Using a continuousvariable (per m2) as opposed todosing based on group (small,medium, large) may make sense.
What About Other Metrics for Dose Calculation/Normalization
Size (kg or BSA)Age
Organ FunctionMetabolismTransporters
Co-MedicationsSex
Variability
Dose PK⎯ →⎯ Exposure PD⎯ →⎯ ResponseSize (kg or BSA) Commonly used as a standard
Age Should older individuals get full doses?
Organ Function Kidney or liver function, cardiac output
Metabolism P450 polymorphism
Transporters ABC transporter polymorphisms
Co-Medications Drugs that compete for metabolism/transport
Sex Sexual dimorphisms
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For carboplatin dosing a target AUC is chosen and the dose in mg calculatedbased on the known relationship between dose/AUC and glomerular filtrationrate
0 10 20 30 40 500
25
50
75
GFR (ml/min)
dose/auc = 1.21 x GFR +23
If you round and solve for dose:
Dose (mg) = AUC (mgxmin/ml) x [GFR(ml/min) + 25 (ml/min)]
Dose Normalization Based on Organ FunctionCarboplatin dosing in humans
This same relationship holds in cats!
This relationship includes a measure oforgan function (GFR) as well as a measureof size (BW) to determine a dose thattargets a specific exposure (AUC)
Dose Calculation based on Transporter Polymorphism Tissue exposures were simulated by PBPK modeling
AUC Serum
AUC Liver
AUC Heart
AUC Gut
AUC Bone Marr
ow
0
20
40
60
80
NormalNull - 30 mg/m2
Null - 10 mg/m2Null - 20 mg/m2
AU
C(0→
t) (n
mol
x h
r/g)
Tissuewt dose equivalent
(mg/m2)WT Dose
%Serum 24.8 ± 3.5 83
Liver 18.2 ± 4.9 61
Heart 23.8 ± 3.9 79
Gut 10.7 ± 5.9 36
This says that you would have to dose reduce from 30 mg/m2 to~11 mg/m2 to have equivalent drug exposure in the gut of nullanimals as opposed to WT animals. If GI toxicity is dose-limiting…. Then this would be required.
Bottom Line on Dose NormalizationAs we learn more about drugs in veterinary populations and as we learn more aboutindividual differences between breeds and species, this information will be incorporatedinto dosing decisions
• Genomics Dataü Polymorphisms
• Pharmacokinetic Data• Response Data
ü Toxicityü Efficacy
• Other Covariatesü Ageü Breedü Sexü Obesityü Organ Function
Population PK Analysis
• Dosing algorithms based oncovariates that have anestablished role in variabilityon exposure
• Populations differentiatedand treated with moreappropriate dosingü Smaller dogs treated with
DOX at 1 mg/kg asopposed to 30 mg/m2 dueto presumed overdosing atthe BSA-based dosing.
How we got where we are with some specific drugs used in veterinary oncology
•Doxorubicin•Cyclophosphamide•Vincristine/Vinblastine• Lomustine•Carboplatin•Toceranib
DoxorubicinBasic Pharmacology
OOH
NH2
OH
OOH
O O
O
OH
O
OH
NHNH
O
NH O
HO OH
OH
HN
HO
HN
O
N NH2
O HN
O
O OO
O
N
N
HN O
O
ON
O
HN OO
ON N
OO
N
Actinomycin D Doxorubicin Mitoxantrone
Mechanism of Action• Inhibition of RNA and DNA polymerases• Topoisomerase II inhibition• Alkylation of DNA• Reactive oxygen generation• Perturbation of cellular Ca2+ homeostasis• Inhibition of thioredoxin reductase• Interaction with plasma membrane components
• Widely distributed to tissues• Metabolized hepatically and extra-hepatically• Single most active agent used in veterinary oncology• Toxicities include GI, hematopoietic, and cardiac toxicity associated with total dose• Can cause severe local tissue damage with extravasation
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Doxorubicin Dosing in DogsToxicity as an endpoint for dose selection
Toxicity (or avoidance of) is inherently the PD endpoint for the current use of cancer chemotherapy in companion animals…. Why?
Where did the dose of 30 mg/m2 for doxorubicin in dogs come from?
First report that I can find of that dose is from:
And they cite the selection of that dose from these studies:
Doxorubicin Indications and Dosing
Most active single agent available• Lymphoma – single agent or combo (CHOP)• Osteosarcoma – single agent or combo (carbo)• Mesenchymal Tumors• Epithelial Tumors
Conventional DosingIV by 10-30 min infusion• 30 mg/m2 q3w in dogs > 15 kg• 1 mg/kg q3w in dogs < 15kg• 1 mg/kg in cats
Doxorubicin Specific Considerations• Extravasation Damage
• Vigilant observation during infusion• Dexrazoxane for treatment• Severity may require surgery and
potential amputation• Cardiac Performance and Monitoring
• Evaluate to detect new murmurs, arrhythmias or pulse deficits
• Cumulative Dose• Ostensibly limited to 120-150 mg/m2
due to cumulative cardiac damage
CyclophosphamideBasic Pharmacology
Mechanism of Action• Binding to DNA• Cross-linking of DNA
through bifunctionalalkylation
• Can be dosed IV, PO or IP• Major dose-limiting side effects are neutropenia and thrombocytopenia• GI toxicity is not common in dogs but has been observed in cats• Hemorrhagic cystitis is uncommon at standard doses but has been observed
CyclophosphamideSpecies-Specific Metabolism
Dogs and cats are actually much more efficient at converting CP to the active 4-OHCP than humans and it is almost entirely attributable to higher affinity for the parent drug CP
Cyclophosphamide Use in Animals
First reported use of CP in treating dog cancers was for treating generalized lymphoma in 1962. They observed some response to the drug at a dose of 2.5 mg/kg. The drug was widely studied in dogs in the 60’s and 70’s for use in organ transplants via immunesuppression. Dose and safety came from those studies as well asstudies in dogs with lymphoma and other neoplasms.
Cyclophosphamide Indications and Dosing
Indications• Lymphoma in dogs (CHOP) • Lymphoma in cats
Conventional DosingBolus by IV or Oral (PO)• 250 mg/m2 q3w in dogs• Fractionated
• 50 mg/m2 3-4 days
• 200-250 mg/m2 IV in cats• Up to 300 mg/m2 PO in cats
Cyclophosphamide Specific Considerations• Hemorrhagic Cystitis
• Furosemide is generally given prior to IV treatment
• Vigorous hydration• Frequent urination
• CP should be discontinued if cystitis occurs• Chlorambucil can be used as a substitute in
multi-agent protocols
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Vinca Alkaloids (Vincristine and Vinblastine)Basic Pharmacology
O
O
OO
OH
OO
O
HO
NH
OH
OO
O
O O
O
OO
HN
O O
O
OO
OHO
O
O
OHOH
H
H
NH
N
HO
H
N
N
OOH
O
O
O
O
O
O
NH
N
HO
H
N
N
O OOH
OO O
O
O
O
Vincristine Vinblastine
Paclitaxel Docetaxel
Mechanism of Action• Binds to tubulin preventing
microtubule assembly• Cells accumulate in G2/M• Cells die by apoptosis or mitotic
catastrophe
• VCR is less myelosuppressive then VBL• VCR is more neurotoxic (peripheral
neurotoxicity)• VCR has greater GI toxicity and can cause
significant ileus
Vinca Alkaloid Indications and DosingIndications• VCR - Lymphoma in dogs (CHOP) • VCR – Transmissible Venereal Tumors
(single agent)• VBL – Mast Cell Tumors (single agent
or in combination)
Conventional Dosing• Vincristine • 0.5 - 0.75 mg/m2 IV bolus weekly in
dogs and cats• Vinblastine• 2.5 mg/m2 every 1-2 weeks• 3.0-3.5 mg/m2 every 2-3 weeks
Vincristine/Vinblastine Specific Considerations• ABCB1 Mutant Dogs
• More susceptible to VCR-induced myelosuppression
Lomustine (CCNU)Basic Pharmacology
PNHN
O OCl
Cl
OH
ON
Cl
Cl
O
N NH
Cl
NO
N
HN
O
H2N
NN
N
PO N
Cl
HN O
Cl
O
OH
NH2NCl
Cl
Cyclophosphamide
Chlorambucil
Lomustine
Dacarbazine
Ifosfamide
Melphalan
NClCl
O
OH
OH
OHHN
HO
N
O
NO
NH
HN
O
NH
Mechlorethamine
Nitrogen Mustards
Streptozotocin
Procarbazine
Nitrosureas
Other Alkylating Agents
Mechanism of Action• Lomustine (CCNU) is highly lipid soluble and
spontaneously decomposes to a reactivecenter capable of DNA binding, DNA-DNAand DNA protein crosslinks
• CCNU undergoes extensive hepaticmetabolism but is orally active due to activemetabolites being formed
• Dose limiting toxicity is myelosuppression with acute neutropenia followed by thrombocytopenia
• Chronic administration may cause hepaticdysfunction requiring temporary or permanent discontinuation of drug
Lomustine Use in Animals
Established activity in the relapse setting for lymphoma and that a dose of 90 mg/m2 had manageable toxicity
Lomustine Indications and Dosing
IndicationsDogs• Multicentric lymphoma (single agent
or in combination)• Epitheliotropic lymphoma• Mast cell tumors• Histiocytic sarcomaCats• Mast cell tumors• Lymphoproliferative disorders
Conventional DosingDogs• 70-80 mg/m2 PO q3w
Cats• 50-60 mg/m2 PO every 4-6 weeks
Lomustine Specific Considerations• Hepatic toxicity may be reduced by
coadministration with denmarin• Denmarin increases glutathione levels and is an
antioxidant and “liver tonic”…… • PK of lomustine is poorly defined due to
extensive metabolism and the presence ofactive metabolites
CarboplatinBasic Pharmacology
ClPt
Cl
NH2
NH2
O
Pt
O
O
O
NH2
NH2
NH
NH2
O
HO
Cisplatin Carboplatin Hydroxyurea• Metabolized primarily through reactions with water and elimination by binding to
plasma and tissue proteins• Measured primarily as total Pt and it is important to differentiate “bound” and
“free” fractions in the plasma• Primarily eliminated in the urine with 65% of the total dose recovered in the urine
24 hours after administration – Thus correlation between AUC and GFR• Myelosuppression is the primary toxicity
Mechanism of Action• Inter- and intra-strand DNA crosslinks• DNA-protein cross-links
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Carboplatin Use in Animals
JVIM 7:235, 1993
Carboplatin was tested in a Phase Istudy in dogs with spontaneoustumors. PK and toxicity wereperformed to determine a safedose. Drug was given as a 30 mininfusion is a dose escalation study.
Analyses looked attoxicity (moderate andsevere) over both the1st and subsequentdoses and determineddoses resulting in 50%moderate tox and 5%severe tox to rangefrom 231 to 340mg/m2. This led to arecommended dose of300 mg/m2 goingforward….
Carboplatin Indications and Dosing
IndicationsDogs• Osteosarcoma (single agent or in
combination with DOX)• Sarcomas• CarcinomasCats• Sarcomas• Carcinomas
Conventional DosingDogs• 300 mg/m2 IV over 10-15 minutes q3w
Cats• 240 mg/m2 IV over 10 minutes q3w
Carboplatin Specific Considerations• Strong correlations exist with carboplatin
exposure and renal function such that dosing can be based on measures of renal function• Individualized dosing means that carboplatin can
be used in cats with overt renal disease using GFR-based dose modifications
Toceranib (Palladia®)Basic Pharmacology
Mechanism of Action• Tyrosine kinase inhibitors• Have activity against a number of receptor tyrosine
kinases including VEGFR, FGFR, PDGFR and Kit• Compete with ATP at the ATP binding site to block
tyrosine kinase activity • Tumor cells that are addicted to the activity of these
RTKs should be especially sensitive to blocking thesesignaling pathways
• Blocks activation of wild-type and mutant Kit• Orally available• Nearly identical to the human drug sunitinib both in
terms of chemistry and activity• First “molecularly targeted agent “ approved for use
in veterinary oncology
Toceranib Studies in Animals
Alternate-day dosing resulted in less toxicity and target serum concentrations could be achieved for 50% of the dosing interval at 2.5-3.25 mg/kg EODTrough Levels
Toceranib Indications and Dosing
IndicationsDogs• Approved for mast cell tumors• Anal sac adenocarcinoma• Gastrointestinal stromal tumors• Thyroid carcinoma• Nasal adenocarcinomaCats• Mast cell
Conventional DosingDogs• 3.25 mg/kg PO q48h• 2.5 – 2.75 mg/kg Mon, Wed, Fri
Cats• 2.7 mg/kg Mon, Wed, Fri
Toceranib Specific Considerations• Toxicities include diarrhea, vomiting, anorexia and GI bleeding. Neutropenia is rare and
mild.• This drug is being tested extensively in the post-approval setting so expect to see numerous
combination therapies including toceranib to be reported.
Toceranib Specific Considerations• Toxicities include diarrhea, vomiting, anorexia and GI bleeding. Neutropenia is rare and
mild.• This drug is being tested extensively in the post-approval setting so expect to see numerous
combination therapies including toceranib to be reported.
The End!
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