pharmacokinetic and pharmacodynamic parameters...

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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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[Dox

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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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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

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[4-O

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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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loph

osph

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Cyclophosphamide

IVIPPO

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4-OH CP

IVIPPO

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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

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[Dox

orub

icin

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m n

g/m

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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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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

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Doxorubicin Dose

DO

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AUC0-6h

AUC/Dose

*P=0.016

PharmacokineticsVariability - Vinblastine

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Vinb

last

ine s

erum

(ng/

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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

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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

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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.


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.


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Relationships Between Drug Exposure and PD ResponseVinblastine PK/PD in Dogs

Nice clear relationship with exposure and neutropenia… All right!!!

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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?


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.

https://www.cancer.gov/about-cancer/treatment/clinical-trials/what-are-trials/phases

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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


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)


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

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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

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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

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NH2

OH

OOH

O O

O

OH

O

OH

NHNH

O

NH O

HO OH

OH

HN

HO

HN

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N NH2

O HN

O

O OO

O

N

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HN O

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ON

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ON N

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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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pharmacokinetic and pharmacodynamic parameters...

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