Principles of Clinical Pharmacology

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Principles ofClinical Pharmacology

• Steven P. Stratton, Ph.D.

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Learning Objectives

• To define Pharmacokinetics Pharmacodynamics
• To identify PK/PD approaches, terminology, and
  parameters
• To consider endpoints for PK/PD modeling
• To identify barriers and opportunities with
  molecularly targeted drugs
• To see new advances in clinical pharmacology
• To understand some practical considerations in
  design 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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Pharmacokinetics
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Pharmacodynamics
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Practical considerations in designing clinical
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 DrugsThings 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 to gain FDA approval?

• Toxicity
• Efficacy
• Pharmacokinetic Properties
• Cost
• Marketing

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Reasons for Attrition During Clinical Development
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40
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Percentage of New Drugs Failing
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0
Other
Safety
PK
Efficacy
Toxicology
Commercial
Formulation
Cost of Goods
Nature Reviews Drug Discovery 2, 566-580 (2003)
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PK Terminology
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Audience Question 2 What is the most
important pharmacokinetic variable?

• Volume of Distribution (Vd)
• Bioavailability (F)
• Clearance (CL)
• Half-life (t1/2)
• Area Under the Curve (AUC)

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Apparent Volume of Distribution (Vd)
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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 bound 10 free ? 11
free Free drug concentration ? 10
Experimental Drug B 99 bound 1 free ? 2
free Free drug concentration ? 100
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Clearance (CL)

• Renal
• Hepatic
• Lung

It hurts when I pee.
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Area Under the Curve (AUC)

• Integration of Conc. vs. Time
• Measure of systemic exposure

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Half-life (t½)

• Time required to clear 50 of drug
• Depends on Volume of Distribution (Vd) and
  Clearance (CL)
• Multi-phasic (if you can capture the distribution
  phase)
• Rule of Thumb Drug is cleared in 5 half-lives

t½ 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 the
  concentration
• AUC not affected by schedule
• Example doxorubicin

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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 one hour, which would be least
likely to result in your dismissal?

• 5 mg oxycodone
• 150 mg erlotinib
• Top-shelf (Patron) margarita
• 4-5 bong hits

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What is Translational Research?
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Translational Research

• the interphase between basic research and its
  application in a clinical setting for the
  diagnosis, treatment, or prevention of a
  disease.
• Dr. William Hait, Past Pres. AACR
• Observation ? Practice
• PK/PD is a cornerstone of translational research

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PK/PD Modeling
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PK Variability in Ovarian Cancer Patients250
mg/m2, 24 hr infusion, 22-23 hr sample, n 48
Cancer Chemother Pharmacol 3348-52 (1993)
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PK/PD modeling of Taxol-induced neutropenia

• Non-linear kinetics
• Myelosuppression related to duration of threshold
  plasma concentration
• Taxol 0.05 mM
• Prediction of disposition and toxicity

Gianni et al J Clin Oncol 13180-190 (1995)
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PK/PD ModelingEffect of formulation on
paclitaxel PK

• First-Order Elimination (Abraxane)
• Rate of elimination is proportional to drug
  concentration
• Constant fraction of drug eliminated per unit time

• Zero-Order Elimination (Taxol)
• Rate of elimination constant regardless of drug
  concentration
• Constant amount of drug eliminated per unit time

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• paclitaxel (Taxol)
• 6 hr infusion, q 21d
• Cremaphor formulation
• Premedication
• Non-linear kinetics
• J Clin Oncology 91261-1267 (1991)

• paclitaxel (ABI_007)
• nanoparticles
• 30 min infusion, q 21d
• No cremaphor
• No premeds
• Linear kinetics
• Clin Cancer Res 81038-1044 (2002)

Stratton Clin Pharm AACR/ASCO Vail 2005
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PD Modeling Example Pharmacogenetics
Myelotoxicity and UGT genetic polymorphisms

• Irinotecan
• 350 mg/m2
• 90 min infusion, q3w
• n 66
• SN-38 metabolism dependent on UGT variant
• Identification of patients predisposed to severe
  irinotecan toxicity

Innocenti et al. J Clin Oncol 221382-1388 (2004)
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Molecularly-targeted Drugs
We found a drug. Now go find something for it
to cure.
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Shift Towards Target-based vs. Compound-based
Development

• Compound-based (backward)
• Interesting compound discovered with activity in
  in vitro models
• Target-based (forward)
• Protein or gene targets identified on
  carcinogenesis pathway.
• Drugs designed to interfere with these specific
  targets

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EGFR as a Molecular Target

• Member of erbB family of receptor tyrosine
  kinases
• 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 in angiogenesis,
  proliferation, and inhibition of apoptosis

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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 targeted EGFR inhibitors

• Mutation in EGFR
• Activation of redundant pathways
• Constitutive activation of downstream signaling
  factors
• Ligand-independent activation of EGFR

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Altered response to EGFR inhibitors
Mutations in the EGFR gene

• EGFR mutations have been characterized in
  gliomas, NSCLC, breast, ovarian cancers
• Activating mutations correlated with increased
  response to gefitinib in NSCLC

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Resistance to EGFR inhibitors
Activation of redundant pathways

• Resistance caused by activation of other tyrosine
  kinase receptors that bypass the EGFR pathway

Camp ER et al, Clin Cancer Res 11397-405 (2005)
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Resistance to EGFR inhibitors
Constitutive activation of pathways downstream of
EGFR
Camp ER et al, Clin Cancer Res 11397-405 (2005)
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Resistance to EGFR inhibitors
Ligand-independent activation of EGFR

• EGFR can be activated by integrins
• cetuximab could not inhibit this pathway

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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 mechanism
• Almost all in vitro mechanisms 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?

• Combinations
• We need better tools to select the best
  patient/therapy combinations

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Pharmacogenomics

• How variations in the genome affect the response
  to medications

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Personalized therapy in ovarian cancer A genomic
approach Dressman et al, JCO 25517 (2007)

• Primary ovarian tumors collected at surgery from
  119 patients
• All patients recd platinum-based therapy
• 85 CR, 34 IR
• DNA microarray analysis
• Gene expression signatures used to predict
  oncogenic pathways activated in a tumor
• Relationship between pathway activation and
  survival was analyzed in CRs and IRs

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Colors represent predicted probability of pathway
activation
Src or E2F3 pathway activation differentiated
survival in Incomplete Responders
Pathway activation had no effect on survival in
Complete Responders
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How is this helpful? Is it real?

• Potential (very cool) application of pathway
  prediction in this patient population

Dressman et al, JCO 25517 (2007)
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Practical Advice in PK Study Design
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Practical Advice in PK Study Design
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Typical Phase 1/PK Study

• Goal
• Capture adequate tissue samples to measure
  drug/metabolite levels over time
• 0, ½, 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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Practical Advice in PK Study Design

• 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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Practical Advice in PK Study Design

• 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
  frozen plasma ? Disaster
• Cheap ink, cheap labels, and freezers dont mix

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Compound-based vs. Target-based Drug Development
Compound-Based Target-Based Compound
isolated Target identified Compound screened
in cell culture Target validated in vitro
Activity in Animal Models Compounds screened for
target selectivity Mechanism
Toxicology Toxicology performed
Clinical Trials Phase I Phase I, II, III
Clinical Trials in Patients Expressing
Target Phase II Phase III