Stratton Clinical Pharmacology

8/22/2019 Stratton Clinical Pharmacology

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Principles of

Clinical PharmacologySteven P. Stratton, Ph.D.


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Learning Objectives

To define Pharmacokinetics & Pharmacodynamics

To identify PK/PD approaches, terminology, andparameters

To consider endpoints for PK/PD modeling

To identify barriers and opportunities withmolecularly targeted drugs

To see new advances in clinical pharmacology

To understand some practical considerations indesign of PK studies in clinical protocols


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Potential Therapeutic Outcomes

Efficacy without toxicity Palliation

Efficacy with toxicity Treatment, potentially curative

Toxicity without efficacy

Poison Neither toxicity nor efficacy

Alternative medicine


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80 mg/m2

Time (min)

0 100 200 300 400 500

PlasmaConcentrations(g

/ml)

0

2

4

6

8

10PT 004

PT 005

PT 006PT 007

LOQ

Pharmacokinetics


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Pharmacodynamics


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Practical considerations in designingclinical drug intervention trials

Why this drug?

What dose?

What schedule?

What combination?

What about other interactions?


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Administering Drugs:

Things to consider Age

Renal status

Liver function Polymorphisms

Cytochrome P450 (genetics, drug interactions)

Acetylator status (genetics)

Target present?


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Administering Drugs:

Things to consider What should I measure?

How do I measure it?

Correct sampling schedule

Validated method available?

and most importantly

What do I do with the answer?


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Audience Question #1:Once in the clinic, what is the primary

reason for failure of experimental drugs togain FDA approval?

A. Toxicity

B. Efficacy

C. Pharmacokinetic Properties

D. CostE. Marketing


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Reasons for Attrition During Clinical Development

Perc

entageofNew

DrugsFailin

g

0

10

20

30

40

50

Nature Reviews Drug Discovery2, 566-580 (2003)


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PK Terminology


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Audience Question #2:

What is the most important

pharmacokinetic variable?

A. Volume of Distribution (Vd)

B. Bioavailability (F)

C. Clearance (CL)

D. Half-life (t1/2)E. Area Under the Curve (AUC)


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Apparent Volume of Distribution (Vd)

Vd =Concentration

Amt of Drug (dose)

Small VdLow tissue binding Large Vd

Drug tightly bound

Concentration =Vd

Amt of Drug (dose)


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Protein Binding

Large fraction of drug bound to tissue

Unavailable for drug function

Easily measured in vitro(% bound)

Consequences

What if bound drug is displaced?

e.g. aspirin, warfarin displaces 1%

Experimental Drug A: 90% bound10% free 11% freeFree drug concentration 10%

Experimental Drug B: 99% bound1% free 2% freeFree drug concentration 100%


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Clearance (CL)

It hurts when I pee.

CL =Concentration

Elimination Rate

RenalHepatic

Lung


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Area Under the Curve (AUC)

Integration ofConc. vs. Time

Measure ofsystemicexposure

AUC

Serum concentration

(mg/mL)


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Half-life (t)

Time required to clear50% of drug

Depends on Volume ofDistribution (Vd) andClearance (CL)

Multi-phasic (if you cancapture the distribution

phase)

Rule of Thumb: Drugis cleared in 5 half-lives

t = Vd x ln(2) / CL


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Other Important Parameters

Peak plasma concentration

Bioavailability

Duration above a threshold concentration

Free drug vs. total drug

Cumulative dose Bioactivation to active metabolite


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PK Analysis

Linear Pharmacokinetics

First order kinetics

Covers most drugs Rate of change depends

only on the current [drug]

Half-life remains constant

no matter how high theconcentration

AUC not affected byschedule

Example: doxorubicin

dC

dt= -kC


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PK Analysis

Non-Linear Pharmacokinetics (zero order)

Classic examples: ethanol, phenytoin

Saturable metabolism Decreased CL at higher doses

Shortened infusion increased AUC

Examples: 5-FU, Taxol

Saturable absorption

Decreased proportional AUC at higher doses

Lengthened infusion increased plasma conc.

Examples: methotrexate, cisplatin


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Audience Question #3:

If you failed to abstain from one of these,

but had to be at work and drug-free in onehour, which would be least likely to resultin your dismissal?

A. 5 mg oxycodone

B. 150 mg erlotinib

C. Top-shelf (Patron) margaritaD. 4-5 bong hits


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What is Translational Research?


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Translational Research

the interphase between basic research andits application in a clinical setting for thediagnosis, treatment, or prevention of adisease.

Dr. William Hait, Past Pres. AACR

Observation Practice

PK/PD is a cornerstone of translationalresearch


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PK/PD Modeling


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Cancer Chemother Pharmacol 33:48-52 (1993)

PK Variability in Ovarian Cancer Patients250 mg/m2, 24 hr infusion, 22-23 hr sample, n = 48

MyelosuppressionLoweredefficacy


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PK/PD modeling of Taxol-

induced neutropenia Non-linear kinetics

Myelosuppression relatedto duration of thresholdplasma concentration [Taxol] 0.05 M

Prediction of dispositionand toxicity

Gianni et al J Clin Oncol13:180-190 (1995)


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PK/PD ModelingEffect of formulation on paclitaxel PK

First-Order Elimination (Abraxane)

Rate of elimination is proportionalto drug concentration

Constant fraction of drugeliminated per unit time

Zero-Order Elimination (Taxol)

Rate of elimination constantregardless of drug concentration

Constant amount of drugeliminated per unit time


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Stratton Clin Pharm AACR/ASCO Vail 2005

paclitaxel (ABI_007) nanoparticles 30 min infusion, q 21d

No cremaphor No premeds Linear kinetics

Clin Cancer Res8:1038-1044 (2002)

paclitaxel (Taxol) 6 hr infusion, q 21d

Cremaphor formulation Premedication

Non-linear kinetics

J Clin Oncology9:1261-1267 (1991)

275 mg/m2

250 mg/m2

175 mg/m2


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Innocenti et al. J Clin Oncol22:1382-1388 (2004)

PD Modeling Example: PharmacogeneticsMyelotoxicity and UGT genetic polymorphisms

Irinotecan

350 mg/m2

90 min infusion, q3w

n = 66

SN-38 metabolismdependent on UGT variant

Identification of patientspredisposed to severeirinotecan toxicity

Grade 4


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We found a drug. Now go find something for it to cure.

Molecularly-targeted Drugs


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Shift Towards Target-based vs.Compound-based Development

Compound-based (backward)

Interesting compound discovered with

activity in in vitromodels

Target-based (forward)

Protein or gene targets identified oncarcinogenesis pathway.

Drugs designed to interfere with thesespecific targets


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EGFR as a Molecular Target

Member of erbB family of receptor tyrosinekinases EGFR (ErbB1), HER2/Neu (ErbB2), HER3 (ErbB3)

and HER4 (ErbB4)

Overexpressed in various solid tumors Overexpression has been correlated with poor

prognosis

EGFR signaling is implicated inangiogenesis, proliferation, and inhibition ofapoptosis


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EGFR Mechanism

Courtesy of Genentech


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EGFR Targeted Therapy

Neutralizing monoclonal antibody cetuximab

competitive inhibitor

prevents dimerization

Tyrosine kinase inhibitors

erlotinib, gefitinib reversible inhibitors

lapatinib duel EGFR/erbB2 irreversible inhibitor


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Issues with molecularly targetedEGFR inhibitors

Mutation in EGFR

Activation of redundant pathways

Constitutive activation of downstreamsignaling factors

Ligand-independent activation of EGFR


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Altered response to EGFR inhibitors

EGFR mutations have been characterized in

gliomas, NSCLC, breast, ovarian cancers

Activating mutations correlated withincreased response to gefitinib in NSCLC

Mutations in the EGFR gene


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Resistance to EGFR inhibitors

Resistance caused by activation of other tyrosine kinase receptorsthat bypass the EGFR pathway

Camp ER et al, Clin Cancer Res11:397-405 (2005)

Activation of redundant pathways


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Constitutive activation of pathways downstream of EGFR

Activating mutations ingenes downstream ofEGFR signaling couldbypass the effect ofthe EGFR inhibitor

Camp ER et al, Clin Cancer Res11:397-405 (2005)


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EGFR can be activated by integrins

cetuximab could not inhibit this pathway

Ligand-independent activation of EGFR


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Concerns with Targeted Therapy

The Butterfly effect Predicting toxicities of a single target is difficult when the

target of interest is relatively upstream in a pathway Example: bortezomib (Velcade) myelosuppression, fatigue,

etc.

Dosing regimens are difficult to determine High potency difficult detection of drug Cytostatic mechanism low toxicity, MED vs. MTD

Targeted therapies are not as specific as we think(e.g., imatinib mesylate, sorafenib) Pleiotropism


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Concerns with Targeted Therapy(contd)

Redundancy Cells that find a way get rewarded and select

for resistance

Delivery (chemistry) The drug may not reach the target in vivo (PK)

Bogus mechanismAlmost all in vitromechanisms are convenient to

believe once the xenograft data is positive

A good (valid) biomarker is hard to find


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How do we improve

targeted therapies?1. Combinations2. We need better tools to select the best

patient/therapy combinations

Personalized Medicine

the future of clinicalpharmacology


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Pharmacogenomics

How variations in the genome affect theresponse to medications

P li d th i i


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Personalized therapy in ovarian cancer:A genomic approach

Dressman et al, JCO 25:517 (2007)

Primary ovarian tumors collected at surgeryfrom 119 patients

All patients recd platinum-based therapy 85 CR, 34 IR

DNA microarray analysis

Gene expression signatures used to predictoncogenic pathways activated in a tumor

Relationship between pathway activationand survival was analyzed in CRs and IRs


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Colors representpredicted probability ofpathway activation

Src or E2F3 pathwayactivation differentiated

survival in IncompleteResponders

Pathway activation hadno effect on survival inComplete Responders


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How is this helpful? Is it real?

Potential (very cool) application of pathwayprediction in this patient population

Dressman et al,

JCO 25:517 (2007)


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Practical Advice in PK Study Design


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I was hoping I could choose my own doctor

Patient Considerations

Its a baby. Regulations prohibit ourmentioning its race, age, or gender.

Regulatory Considerations



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Typical Phase 1/PK Study

Goal

Capture adequate tissue samples to

measure drug/metabolite levels over time 0, , 1, 2, 4, 8, 24, 48 hr

Day 8, Day 15

Capture 4-5 half-lives if possible May need to collect urine, other fluids?


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Know your analyst Ensure that the analytical technique is available Ensure that the method is available, validated, and reliable Define sample preparation

Know your sample size The biometrist is your friend visit them early and often

Be kind to nurses Do you really want that 16 hr PK? Dont require a sample at the end of the infusion- too

many things at once is trouble



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Consider your patients Dont exsanguinate them

Extended PK sampling can be exhausting

Dont sample from the infusion port

Define and monitor sample handling!! Ensure study personnel are informed and understand

SOPs

Shipping whole blood at room temp instead of frozenplasma Disaster

Cheap ink, cheap labels, and freezers dont mix



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Compound-Based Target-Based

Compound isolated Target identified

Compound screened in cell culture Target validated in vitro

Activity in Animal Models Compounds screened fortarget selectivity

Mechanism ToxicologyToxicology performed

Clinical TrialsPhase I Phase I, II, III Clinical Trialsin Patients Expressing Target

Phase II

Phase III

Compound-based vs. Target-basedDrug Development

Documents

Stratton Clinical Pharmacology