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

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

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

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.

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

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

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

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

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…”

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

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)

Camptosar Label Revised and Camptosar Label Revised and FDA Approved UGT TestFDA Approved UGT Test

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.

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

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

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

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

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)

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

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

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

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

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

Benefit: INR and Stroke PreventionBenefit: INR and Stroke Prevention

Hirsch, J Amer Coll Cardio 41:1633-1652, 2003

Risk: INR and Intracranial HemorrhageRisk: INR and Intracranial Hemorrhage

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

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

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

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

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

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

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

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

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

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

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

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

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

AcknowledgementsAcknowledgements

Dr. Myong-Jin Kim

Dr. Felix Frueh

Dr. Shiew-Mei Huang

Dr. Atik Rahman

Review of Genotype Data in Labels Generally and Evidence Related to Warfarin Specifically

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