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![Page 1: Introduction Lawrence J. Lesko, Ph.D., FCP Director of the Office of Clinical Pharmacology and Biopharmaceutics Center for Drug Evaluation and Research.](https://reader035.fdocuments.in/reader035/viewer/2022062805/5697c00d1a28abf838cc921f/html5/thumbnails/1.jpg)
IntroductionIntroduction
Lawrence J. Lesko, Ph.D., FCPDirector of the Office of Clinical Pharmacology and BiopharmaceuticsCenter for Drug Evaluation and ResearchFood and Drug Administration
Clinical Pharmacology Subcommittee (CPSC) of the Advisory Committee for Pharmaceutical SciencesNovember 14-15, 2005Rockville, Maryland
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CPSC Meeting HistoryCPSC 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 IRecent 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 IIRecent 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 MeetingThis Meeting
1.Pharmacogenomic Data in Product Labels- best way to include PGx data in product labels- evidence for including PGx data in warfarin label
2.Model-Based Drug Development- recap experience with EOP2A meetings- stratification issue using clinical trial simulation
3.Biomarkers and Individualization- update on critical path initiatives- including biomarker data in product labels
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Drug Labeling: The Legal Basis Drug Labeling: The Legal Basis of Prescribingof 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 CommonLabel 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 LimitationsLabel 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 closely
Lack of perfect evidence (e.g., specific dose reductions) is not a reason to support inaction
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Irinotecan: November 3, 2004Irinotecan: 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-38Problem: 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 GenotypeRisk 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?
Patient Group Prevalence Risk of Neutropenia
All PatientsNo Test
----- 10 in 100
Wild-type6/6 Genotype
50% 0 in 100
Heterozygous-deficient6/7 Genotype
40% 12 in 100
Homozygous-deficient7/7 Genotype
10% 50 in 100
From Innocenti et al in Clin Pharmacol Ther (2004)
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Camptosar Label Revised and Camptosar Label Revised and FDA Approved UGT TestFDA 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 Therapy:Success and Failure of Drug Therapy:Inborn Predisposition or SusceptibilityInborn 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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WarfarinWarfarin
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 Rx’s over past 10 years especially in the elderly
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Trends in Warfarin Use: 1.5-fold Trends in Warfarin Use: 1.5-fold Increase (45%) in Last 6 YearsIncrease (45%) in Last 6 Years
Prescriptions Dispensed in the U.S. for Warfarin Tablets and Vials
10
15
20
25
30
1998 1999 2000 2001 2002 2003 2004 YTD9/2005
Year
Dis
pe
ns
ed
Rx
(m
illio
ns
)
Source: IMS Health National Prescription Audit Plus TM Data Extracted 11/2005
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EfficacyEfficacy of Warfarin 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 139:893-900, 2003Schulman, N Engl J Med 349:675-683, 2003Eikelboom, Med J Australia 180:549-551, 2004
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Global Problem of Warfarin AEsGlobal 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 39:1161-1168, 2005Wadelius, The Pharmacogenomics J, 5:262-270, 2005Pirmohamed (Personal Communication)
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SafetySafety of Warfarin 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 349:675-683, 2003Pirmohamed, British Med J 329:15-19, 2004DaSilva, Seminars Vasc Surg 15:256-267, 2002Eikelboom, Med J Australia 180:549-551, 2004
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DosingDosing of Warfarin is Complex 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 PK of Warfarin: Mechanistic Basis of of Warfarin: Mechanistic Basis of Dosing ProblemDosing Problem
Large interindividual variability related to S-warfarin metabolism by CYP2C9 (genetics)– *1 (wild type), *2 and *3 (variant alleles)
Genotype(N = 188)
Prevalence % Enzyme Activity
S/R Warfarin(mg/L)
Weekly Doses(mg)
Clearance/LBW
(ml/min/kg)
2C9 *1/*1 63% 100% 0.45 (0.11)
34.1(19.5)
0.065 (0.025)
2C9 *1/*X 31% 50-70% 0.69(0.28)
19.0(10.8)
0.041 (0.021)
2C9 *X/*X 6% 10% 1.43(0.63)
11.5(7.2)
0.020 (0.011)
Herman et al, The Pharmacogenomics J 4:1-10. 2005
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Dosing Adjustments Based on Genotype-Dosing Adjustments Based on Genotype-Specific S-Warfarin ClearanceSpecific S-Warfarin Clearance
0%
20%
40%
60%
80%
100%
PDR
Reco
mm
ende
d Do
se,
%Wild Type *1/*2 *1/*3 *2/*2 *3/*3
Equivalent Warfarin Doses in Common Genotypes
Stefanovic and Samardzija, Clin Chem & Lab Med, 42(1) 2004
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PDPD of Warfarin: Mechanistic Basis of of Warfarin: Mechanistic Basis of Variability in ResponseVariability in Response
INR: measure of intensity of anticoagulation– Dose-plasma levels-INR
Plasma warfarin was a strong predictor of changes in INR measurements (p < 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 58:588-93, 1995
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Benefit: INR and Stroke PreventionBenefit: INR and Stroke Prevention
Hirsch, J Amer Coll Cardio 41:1633-1652, 2003
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Risk: INR and Intracranial HemorrhageRisk: INR and Intracranial Hemorrhage
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Unequivocal Association Between 2C9 Unequivocal Association Between 2C9 Alleles and Warfarin-Induced BleedingAlleles and Warfarin-Induced Bleeding
Higashi, JAMA 287:1690-1698, 2002Margaglione, Thromb Haemost 84, 775-778, 2000Ogg, The Lancet 354:1124, 1999Sanderson, Genetics in Medicine, 7:97-104, 2005
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Quality of Anticoagulation is Generally Quality of Anticoagulation is Generally Poor Despite INR MonitoringPoor 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 (>70% time in target INR range)
Davis, Annals of Pharmacotherapy, 39:632-636, 2005Lin, Europ Soc Cardiology, 7:15-20, 2005Menzin, Annals of Pharmacotherapy, 39:446-451, 2005Peterson, J Am Coll Cardiol, 41:1445-1451, 2003
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Two Phases of Warfarin DosingTwo 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 PhaseInitial Dosing During Induction Phase
Initial dose: estimated maintenance dose (5 mg/day) based on patient co-factors
Predictors of higher (> 5 mg/day) doses – Indication, e.g., cardiac replacement valves– Co-morbidities, e.g., diabetes– Age < 55 y– Male gender– African-American ethnicity– Vitamin K intake– Weight– Concomitant drugs, e.g., carbamazepine
Absher, Annals of Pharmacotherapy 36:1512-1517, 2002Hillman, Pharmacogenetics 14:539-547, 2004
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Individualize dosing based on rise in INR
INR Monitoring During Induction INR Monitoring During Induction PhasePhase
• 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 KDependent
Clotting Factors
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Schematic of Warfarin Dosing: One Schematic of Warfarin Dosing: One Size Fits FewSize Fits Few
Initial Dose: 35 mg/week
AgeGenderBSAConcomitant DrugsCo-morbidities
30-35% 20-25%
INR
2
3
Increase DOSE Decrease
Repeat INR: Adjust Dose
Stable Maintenance Dose
INR
2
3
29 mg/wk
28 mg/wk
24 mg/wk
18 mg/wk
6 mg/wk
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Clinical Example: Problem with Initial Clinical Example: Problem with Initial Anticoagulation Rate and INR MonitoringAnticoagulation 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, 2C9*2/2C9*3
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Implications of Difficult Induction Implications of Difficult Induction Phase for Patients with 2C9 AllelesPhase 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
Peyvandi, Clin Pharmacol Ther 75:198-203, 2004Aithal, The Lancet, 353: 717:719, 1999
2C9 *2 and *3 unequivocally risk factors consistently across studies; magnitude of
risk increase is variable
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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.
Risks of Warfarin Are Greatest During Risks of Warfarin Are Greatest During Induction PhaseInduction Phase
Schmelzer (Marshfield Clinic), Report to Agency for Healthcare Research and Quality (AHRQ), 2001
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Frequency of Major Bleeds Following Frequency of Major Bleeds Following Initiation of Warfarin DosingInitiation of Warfarin Dosing
0.0%
0.5%
1.0%
1.5%
2.0%
2.5%
3.0%
Fre
qu
ency
(
% /
mo
nth
)
Up To 4 Weeks Up to 52 Weeks After 52 Weeks
Major Bleeding with Outpatient Warfarin
Landefeld, Am J Med 87:144-152, 1989
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Prospective Genotyping of CYP 2C9: Prospective Genotyping of CYP 2C9: Translation of Data to PracticeTranslation of Data to Practice
Would knowledge of a patient’s 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 Incremental Value: Accounting for Interpatient Variability in DosingInterpatient Variability in Dosing
Reference 2C9 Alleles Alone All Other Factors*
Herman, 2005 27% 10%
Wadelius, 2005 12% 18%
Hillman, 2004 20% 27%
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 Can Genotyping Data in Label Help Anticoagulation During Induction Phase?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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AcknowledgementsAcknowledgements
Dr. Myong-Jin Kim
Dr. Felix Frueh
Dr. Shiew-Mei Huang
Dr. Atik Rahman
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Review of Genotype Data in Labels Generally and Evidence Related to Warfarin Specifically
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