Lawrence J. Lesko, Ph.D., FCP Director of the Office of Clinical Pharmacology and Biopharmaceutics C

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Introduction
Clinical Pharmacology Subcommittee (CPSC) of the
Advisory Committee for Pharmaceutical
SciencesNovember 14-15, 2005Rockville, Maryland

• Lawrence J. Lesko, Ph.D., FCPDirector of the
  Office of Clinical Pharmacology and
  BiopharmaceuticsCenter for Drug Evaluation and
  ResearchFood and Drug Administration

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CPSC Meeting History

• November 2-3, 2002
• April 22-23, 2003
• November 17-18, 2003
• November 3-4, 2004
• November 14-15, 2005

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Recent CPSC Topics I

• Quantitative methods
• M/S to optimize dosing adjustments and reduce
  risk in patient subgroups
• Pharmacogenomics
• Label revisions of thiopurines and irinotecan to
  include genomic data for guiding dosing
• Evaluation of drug interactions
• Labeling and evaluation of enzyme and transporter
  mechanisms for guidance revision

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Recent CPSC Topics II

• Critical path initiatives
• End-of-phase 2A (EOP2A) meetings
• Framework for biomarker evaluation

Opportunity .. Biomarkers to target
responders, monitor clinical response and
measures of drug effectiveness.
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This Meeting

• Pharmacogenomic Data in Product Labels- best way
  to include PGx data in product labels- evidence
  for including PGx data in warfarin label
• Model-Based Drug Development- recap experience
  with EOP2A meetings- stratification issue using
  clinical trial simulation
• Biomarkers and Individualization- update on
  critical path initiatives- including biomarker
  data in product labels

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Drug Labeling The Legal Basis of Prescribing
If evidence is available to support the safety
and effectiveness of the drug only in selected
subgroups of the larger population with a
disease, the labeling shall describe the evidence
and identify specific tests needed for selection
and monitoring of patients who need the
drug. - 21 CFR 201.57
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Label Revisions Are Common

• Labels among most frequently consulted
  information sources
• Label updates one of the main tools for informing
  physicians and patients about new risks
• Original version reflects pre-approval data
• Efficacy documented safety provisional
• New insights post-approval alter B/R and drive
  regular label revisions
• Particularly important for individualizing
  therapy

Martin-Facklam, Eur J Clin Pharmacol 2004
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Label Revisions Have Limitations
While physicians wish for precise management
advice, e.g., specific dose adjustments, evidence
may sometimes be descriptive and actions general,
e.g., reduce the dose, titrate carefully or
monitor more closelyLack of perfect evidence
(e.g., specific dose reductions) is not a reason
to support inaction
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Irinotecan November 3, 2004

• IrinotecanR (camptosar) proven 1st (5-FU and
  leucovorin) and 2nd line therapy for metastatic
  colon/rectal cancer
• Providers/patients face a clinical predicament
  what is the optimal dose
• Incidence of grade 3-4 neutropenia is 35
• Nearly 70 of patients need dose reduction
• Toxicity associated with SN-38 exposure

causes severe myelosuppression ...death due
to sepsis following myelosuppression ...adjust
doses based on neutrophil count
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Problem Accumulation of SN-38

• Exposure dependent on metabolism of SN-38 by
  UGT1A1
• Wide interpatient variability in UGT1A1 activity
• Patients with 28 variant (7 TA repeats) have
  reduced enzyme activity
• Homozygous deficient (7/7 genotype) patients have
  the greatest risk of neutropenia
• Neutropenia matters to patients
• Original label was silent on UGT information
  approved dose not optimized

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Risk Assessment by Genotype

• Would an adjunct UGT diagnostic test to identify
  patients who are 7/7 genotype lead to lower risk
  of neutropenia vs SOC?

From Innocenti et al in Clin Pharmacol Ther
(2004)
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Camptosar Label Revised and FDA Approved UGT Test
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Optimizing Warfarin Benefit/Risk with CYP 2C9
Genotypes There has been over 20 label revisions
for warfarin since 1954. The most recent
revision in September 2005 had to due with
interactions with cranberry juice and proton pump
inhibitors.
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Success and Failure of Drug TherapyInborn
Predisposition or Susceptibility
By nature, men are nearly alike by practice,
they get to be wide apart.
Confucius, Analects
Chinese Philosopher
551 BC 479 BC
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Warfarin

• Discovered 60 years ago and one of the most
  widely prescribed drugs in the world
• Intended to prevent and treat thromboembolisms
• Afib, recurrent stroke, DVT, pulmonary embolism,
  heart valve prosthesis
• Multi-source anticoagulant
• 1, 2, 2.5, 3, 4, 5, 6, 7.5 and 10 mg tablet
  strengths
• Significant increase in Rxs over past 10 years
  especially in the elderly

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Trends in Warfarin Use 1.5-fold Increase (45)
in Last 6 Years
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Efficacy of Warfarin
Prospective clinical trials unequivocally
demonstrate effectiveness Mortality risk in
untreated patients with AFib is 2.5X greater than
in warfarin-treated patients Risk of ischemic
stroke in patients with AFib treated with
warfarin is reduced by 65 NNT (vs placebo) to
prevent one stroke 32
Linkins et al, Ann Intern Med 139893-900,
2003Schulman, N Engl J Med 349675-683,
2003Eikelboom, Med J Australia 180549-551, 2004
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Global Problem of Warfarin AEs
2 million people in the US receiving warfarin
near the top in most surveys of AEs 70,000
patients in Sweden receiving warfarin it tops
the list of drug-induced AEs 600,000 patients
in UK receiving warfarin 6 of patients over 80
years 10-24 episodes of hemorrhage per 100
patients Account for 3.6 of all drug-induced
AEs (4th ranked drug) but 15.1 of all severe AEs
(2nd to digoxin) over 10 year period
Evans, Annals of Pharmaco 391161-1168,
2005Wadelius, The Pharmacogenomics J, 5262-270,
2005Pirmohamed (Personal Communication)
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Safety of Warfarin
Major risk is bleeding frequent and severe 1.2
7 major bleeding episodes per 100
patients Responsible for 1 in 10 hospital
admissions Relative risk of fatal extracranial
bleeds 0 - 4.8 NNH for major bleed 333
Schulman, N Engl J Med 349675-683,
2003Pirmohamed, British Med J 32915-19, 2004
DaSilva, Seminars Vasc Surg 15256-267,
2002Eikelboom, Med J Australia 180549-551, 2004
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Dosing of Warfarin is Complex

• Narrow therapeutic index
• Small separation between dose-response curves for
  preventing emboli and excess coagulation
• Nonlinear dose-response (INR)
• Small changes in dose may cause large changes in
  INR with a time lag
• Wide range (50x) of doses (2-112 mg/week) to
  achieve target INR of 2-3
• Patient intrinsic and extrinsic factors

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PK of Warfarin Mechanistic Basis of Dosing
Problem

• Large interindividual variability related to
  S-warfarin metabolism by CYP2C9 (genetics)
• 1 (wild type), 2 and 3 (variant alleles)

Herman et al, The Pharmacogenomics J 41-10. 2005
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Dosing Adjustments Based on Genotype-Specific
S-Warfarin Clearance
Stefanovic and Samardzija, Clin Chem Lab Med,
42(1) 2004
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PD of Warfarin Mechanistic Basis of Variability
in Response

• INR measure of intensity of anticoagulation
• Dose-plasma levels-INR
• Plasma warfarin was a strong predictor of changes
  in INR measurements (p lt 0.0001)
• Accounted for 15.3 of variance in effects of
  warfarin
• Wide interindividual variability with stronger
  correlations at higher INR values
• Response to given INR is also variable
• Difficulty in achieving target INR and frequency
  of AEs shows the limitations of INR

White, Clin Pharmacol Ther 58588-93, 1995
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Benefit INR and Stroke Prevention
Hirsch, J Amer Coll Cardio 411633-1652, 2003
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Risk INR and Intracranial Hemorrhage
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Unequivocal Association Between 2C9 Alleles and
Warfarin-Induced Bleeding
Higashi, JAMA 2871690-1698, 2002Margaglione,
Thromb Haemost 84, 775-778, 2000Ogg, The Lancet
3541124, 1999Sanderson, Genetics in Medicine,
797-104, 2005
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Quality of Anticoagulation is Generally Poor
Despite INR Monitoring
Mean time patients (n 600) spend within
target INR range was 62. More time below (25)
than above (13). Target INR range (n 100) was
achieved on 44 of time. Sub-therapeutic levels
(38) exceeded supra-therapeutic levels
(18) Only 14 (n 52) of patients met criteria
for quality anticoagulation control (gt70 time in
target INR range)
Davis, Annals of Pharmacotherapy, 39632-636,
2005Lin, Europ Soc Cardiology, 715-20,
2005Menzin, Annals of Pharmacotherapy,
39446-451, 2005Peterson, J Am Coll Cardiol,
411445-1451, 2003
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Two Phases of Warfarin Dosing
Induction Phase When initiating warfarin
treatment to achieve target INR (2-3) - daily,
bi-weekly, weekly INR - frequent dose
adjustments in response to INR - reach INR
target in 4-5 days on average - may take 7 30
days to reach steady state Maintenance Phase
When target INR (2-3) is achieved - following
the induction phase - monthly INR, relatively
stable doses - dose adjustments needed based on
changes in co-variates
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Initial Dosing During Induction Phase

• Initial dose estimated maintenance dose (5
  mg/day) based on patient co-factors
• Predictors of higher (gt 5 mg/day) doses
• Indication, e.g., cardiac replacement valves
• Co-morbidities, e.g., diabetes
• Age lt 55 y
• Male gender
• African-American ethnicity
• Vitamin K intake
• Weight
• Concomitant drugs, e.g., carbamazepine

Absher, Annals of Pharmacotherapy 361512-1517,
2002Hillman, Pharmacogenetics 14539-547, 2004
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INR Monitoring During Induction Phase

• Individualize dosing based on rise in INR

• Initial doses suppress factor VII with little
  effect on factors II, IX, X
• INR may appear to reach stable target in 3-5
  days
• Continued dosing inhibits factors with longer
  t1/2 (II, IX, X) resulting in over-shooting
  target INR
• INR in first 4 days have a 65 success rate in
  predicting dose

Vitamin KDependentClotting Factors
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Schematic of Warfarin Dosing One Size Fits Few
29 mg/wk
28 mg/wk
24 mg/wk
18 mg/wk
6 mg/wk
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Clinical Example Problem with Initial
Anticoagulation Rate and INR Monitoring
-Elderly woman in nursing home-Sent to ER with
lower GI bleed-Dx with femoral v
thrombosis-Started warfarin 5 mg/day-After 7
days, INR was 2.5-Advised to continue for 12
wks-INR of 66, treated, discharged-4 days
later, hospitalized-Unexpected rise in INR
7.5-No changes in drug, diet-No medication
errors-Warfarin half-life 10 days
CYP2C9 PGx analysis heterozygote, two variant
alleles, 2C92/2C93
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Implications of Difficult Induction Phase for
Patients with 2C9 Alleles

• More frequent changes in daily dose
• Delayed stabilization and hospital discharge
• Multiple visits to clinic or hospital
• Additional investigation to seek solution
• Increased risk of bleeding

2C9 2 and 3 unequivocally risk factors
consistently across studies magnitude of risk
increase is variable
Peyvandi, Clin Pharmacol Ther 75198-203,
2004Aithal, The Lancet, 353 717719, 1999
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Risks of Warfarin Are Greatest During Induction
Phase
Incorrect dosing, especially during the induction
phase, carries a high risk of either severe
bleeding (too high) or failure to prevent
thromboembolisms (too low).The majority of
warfarin-related AEs occur during the first 30
days of therapy and are preventable with optimal
dosing.
Schmelzer (Marshfield Clinic), Report to Agency
for Healthcare Research and Quality (AHRQ), 2001
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Frequency of Major Bleeds Following Initiation of
Warfarin Dosing
Landefeld, Am J Med 87144-152, 1989
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Prospective Genotyping of CYP 2C9 Translation
of Data to Practice
Would knowledge of a patients genotype improve
warfarin dosing during the induction phase and
reduce the incidence of warfarin-related adverse
events, i.e., unintentional bleeding (overdosing)
and embolisms (underdosing)?
Note Genotyping is not a replacement for other
co-factors but as an additional piece of
information
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Incremental Value Accounting for Interpatient
Variability in Dosing
Relative of Variability in Dose Explained
Age, body weight/BSA, indication, gender,
interacting drugs VKORC 1 SNPs not included
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Can Genotyping Data in Label Help Anticoagulation
During Induction Phase?

• Identify high risk patients for AE (e.g., 2C9 X)
  at risk prior to or during induction phase
• No need to delay initial dosing
• More conservative dose increases
• More frequent INR measurements
• Lower target maintenance dose
• Identify patients likely to require higher
  maintenance doses (e.g., 2C9 1/1)
• Identify low risk patients in need of
  anticoagulation
• Select warfarin alternatives, e.g., aspirin
• Investigations of unexpected toxicity or
  resistance

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Acknowledgements
Dr. Myong-Jin Kim Dr. Felix Frueh Dr. Shiew-Mei
Huang Dr. Atik Rahman
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Next
Review of Genotype Data in Labels Generally and
Evidence Related to Warfarin Specifically