# Presentation: 624080

## Introduction

- 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 History

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

## 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

## 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.*

## 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

## 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***

## 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****** ***

## 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

## 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...”***

## 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

## 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?

| Patient Group | Prevalence | Risk of Neutropenia |
| --- | --- | --- |
| All PatientsNo Test | ----- | 10 in 100 |
| Wild-type6/6 Genotype | 50% | 0 in 100 |
| Heterozygous-deficient6/7 Genotype | 40% | 12 in 100 |
| Homozygous-deficient7/7 Genotype | 10% | 50 in 100 |

***From Innocenti et al  in Clin Pharmacol Ther (2004)***

## Camptosar Label Revised and FDA 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:Inborn 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***

## 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 Rx’s over past 10 years especially in the elderly

## Trends in Warfarin Use:  1.5-fold Increase (45%) in Last 6 Years

## 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 139:893-900, 2003******Schulman, N Engl J Med 349:675-683, 2003******Eikelboom, Med J Australia 180:549-551, 2004***

## 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 39:1161-1168, 2005******Wadelius, The Pharmacogenomics J, 5:262-270, 2005******Pirmohamed (Personal Communication)***

## 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 349:675-683, 2003******Pirmohamed, British Med J 329:15-19, 2004***

***DaSilva, Seminars Vasc Surg 15:256-267, 2002******Eikelboom, Med J Australia 180:549-551, 2004***

## 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*

## 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)

| 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-Specific S-Warfarin Clearance

**Dosing Adjustments Based on Genotype-Specific S-Warfarin Clearance**

***Stefanovic and Samardzija, Clin Chem & Lab Med, 42(1) 2004***

## 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 < 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 Prevention

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

## Risk:  INR and Intracranial Hemorrhage

## Unequivocal Association Between 2C9 Alleles and Warfarin-Induced Bleeding

***Higashi, JAMA 287:1690-1698, 2002******Margaglione, Thromb Haemost 84, 775-778, 2000******Ogg, The Lancet 354:1124, 1999******Sanderson, Genetics in Medicine, 7:97-104, 2005***

## 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 (>70% time in target INR range)

***Davis, Annals of Pharmacotherapy, 39:632-636, 2005******Lin, Europ Soc Cardiology, 7:15-20, 2005******Menzin, Annals of Pharmacotherapy, 39:446-451, 2005******Peterson, J Am Coll Cardiol, 41:1445-1451, 2003***

## 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*

## Initial 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, 2002******Hillman, Pharmacogenetics 14:539-547, 2004***

## Individualize dosing based on rise in INR

**INR Monitoring During Induction Phase**

-  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 K****Dependent****Clotting Factors**

## Schematic of Warfarin Dosing:  One Size Fits Few

***29 mg/wk***

***28 mg/wk***

***24 mg/wk***

***18 mg/wk***

*** ******6 mg/wk***

## 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, 2C9*2/2C9*3**

## 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

***Peyvandi, Clin Pharmacol Ther 75:198-203, 2004******Aithal, The Lancet, 353: 717:719, 1999***

*2C9 *2 and *3 unequivocally risk factors consistently across studies;  magnitude of risk increase is variable  *

## Risks of Warfarin Are Greatest During Induction Phase

**Risks of Warfarin Are Greatest During Induction Phase**

***Schmelzer (Marshfield Clinic), Report to Agency for Healthcare Research and Quality (AHRQ), 2001***

## Frequency of Major Bleeds Following Initiation of Warfarin Dosing

***Landefeld, Am J Med 87:144-152, 1989***

## Prospective Genotyping of CYP 2C9:  Translation 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 Interpatient 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 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

## Acknowledgements

- Dr. Myong-Jin Kim
- Dr. Felix Frueh
- Dr. Shiew-Mei Huang
- Dr. Atik Rahman

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