# Presentation: 864435

## Pharmacogenetics (PG):  Drug Metabolism and Dosage

**Lawrence J. Lesko, Ph.D.****Director, Office of Clinical Pharmacology and Biopharmaceutics****Center for Drug Evaluation And Research****Food and Drug Administration****FDA Science Board****Rockville, Maryland****April 9, 2003**

## The Proposition of the Usual Dose

**Paracelsus**
**(1493-1541)**

**“****The dose makes the poison”**

## Paradox of Modern Drug Development 

**1.  Clinical trials provide evidence of efficacy and safety at **_**usual doses**_** in *****populations***

## The Problem of Variability

**“****Variability is the law of life, and ****as no two faces are the same, ****so no two bodies are alike, ****and no two individuals react alike,****and behave alike under the ****abnormal conditions which we ****know as disease.”**

**Sir William Osler**
**(1849-1919)**

## Paradox of Modern Drug Development 

**1.  Clinical trials provide evidence of efficacy and safety at **_**usual doses**_** in *****populations******2.******  *****Physicians treat *****individual *****patients who can **_**vary widely**_** in their response to drug therapy**

## How Can The Causes of Variability be Unraveled?

***How Can The Causes of Variability be Unraveled?***

## Pharmacogenomics Strategy Applied to the Practice of Medicine

***From McLeod and Evans, Ann Rev of Pharmacol and Toxicol, 2001: 41,101-121 ***

## Pharmacogenomics Strategy Applied to Drug Development

***Pharmacogenomics Strategy Applied to ******Drug Development***

**Drug Discovery**

**Drug Therapy**

**Drug Selection**

**Targets**

**Dosing**

**Class**

**Cause of Disease**

**Differential Diagnosis**

**By 2010**

**By 2005**

**By 2008**

## During Drug Development:  This May Reduce Attrition

**0**

**20**

**40**

**60**

**80**

**100**

**Preclinical**

**Phase 1**

**Phase 2**

**Phase 3**

**NDA**

## During Drug Development:  This May Increase Probability of Success

## During Drug Development:  This May Identify Failures in Advance

***During Drug Development:  This May Identify Failures in Advance***

## PK Basis for Differences in Drug Response

**Extrinsic factors**
- environment (smoking, diet, alcohol)
- drug interactions (Rx, OTC and herbal)
**Intrinsic factors**
- demographic (gender, age, race)
- disease (renal, hepatic)
- _pharmacogenetics (PGt)_
- polymorphisms in genes encoding metabolic enzymes

## PGt and Drug Metabolism

- Patient A

- Patient B

*Wild type*

*Mutation*

**Wild type**

- Concentration

**Mutation**

- Concentration

- Time

- Time

**CYP450**

**CYP450**

** ****Same dose but different plasma concentrations**

***PGt and Drug Metabolism***

## Many CYP450 Enzymes Are Polymorphic:  Example CYP 2D6

-  Responsible for metabolism of 40% of all Rx drugs
-  Over 300 million Rx’s for drugs with polymorphism per year

## PGt:  Possible Impact on PK and Dose-Response

**Efficacy****:  reduction in anxiety and symptoms of depression**

**Safety****:  tachycardia, arrhythmias and drowsiness**

**Example:  Nortriptyline**

## Inherited Activity of CYP 2D6 and Nortriptyline Dosing 

***Inherited Activity of CYP 2D6 and Nortriptyline Dosing****** ***

**Nortriptyline Plasma Levels**

**PM**

**EM**

**IM**

**Consequences:  discontinue medication (ADR, lack of efficacy), delay to relief of symptoms (suicide), premature switch to other medications**

**Doses need for****equivalent exposure**

## Pharmacogenomics in the PDR

- Search of the electronic 2003 version of the PDR containing 2000 entries identified 51 labels containing pharmacogenomic information.
- In most cases, the information could not be easily translated to clinical practice.

## An Informative Label:  Thioridazine (MellarilR)

**Contraindications**
- thioridazine is contraindicated in patients, comprising 7% of the normal population, who are known to have a genetic defect leading to reduced levels of P450 2D6
**Warnings**
- certain circumstances may increase the risk of torsade de pointes...its use in patients with reduced activity of P450 2D6

## Pharmacogenomics During Drug Development

***Pharmacogenomics During Drug Development***

**80% of new clinical trials include *****collection***** of samples for DNA analysis**

***Pharmaceutical R&D Source Book and PhRMA PG WG***

## Informal Survey of PG in INDs and NDAs

***Informal Survey of PG in INDs and NDAs***

***Wendy Chou, Ph.D. and Others OCPB, FDA (ASCPT Poster, Thursday, April 3, 2003)***

## Breakdown of Genotyping and Phenotyping in FDA Survey

-  Genotyping and phenotyping  performed in some submissions
-  Phase II enzymes measured: NAT-2, UGT, GSTM1, etc
-  Receptors: Dopamine, 5-HT, beta-adrenergic, alpha-1 adrenergic, potassium channels, etc
-  Others: HMC, CETP, ACE, alpha-reductase, AAG, CYP2B6, glyceraldehyde 3 -phosphate  dehydrogenase, ApoE etc.

## A Recent Example of a More Informative Label:  Atomoxetine (StraterraR)*

**Human PK**
- A fraction of the population are PM’s resulting in ...
**Drug-Drug Interactions**
- Inhibitors of CYP2D6 in EM’s increase exposure...similar to PM’s
**Adverse Reactions**
- The following ADR’s were either twice as frequent or statistically significantly more frequent in PM’s compare to EM’s...
**Laboratory Tests**
- Laboratory tests are available to identify CYP 2D6 PM’s

** Approved by FDA’s Neuropharmacology Division in January 2003*

## Pharmacogenomics Strategy Applied to Drug Dosing

**Determine alleles of polymorphic CYP enzymes to determine dose and dosage regimens**

**“****We continue to be concerned that ****despite the widespread availability of ****simple PG tests to determine a patient’s**** genotype with regard to CYP 450 enzymes, ****there has been little use of this information ****to tailor drug dosing...”**

***Lesko and Woodcock, The Pharmacogenomics Journal 2, 20-24, 2002***

## During Drug Therapy PGt May Reduce Adverse Events

**28% of hospitalized patients have drug-related ADRs...**Miller et al, Am. J. Hosp. Pharm 30, 584, 1973
**17% of hospitalized children have drug-related ADRs...**Mitchell et al, Am. J. Epid. 110, 196, 1979
**overall incidence of drug-related ADRs is 7%...**Lazarou et al, JAMA, 279, 1200, 1998
**cost of drug-related morbidity and mortality is $177 billion...**Ernst et al, J. Am. Pharm. Assoc., 41, 192, 2001

## Scientific Basis for Using PGt

**Top 27 drugs frequently cited in ADR reports**
- 59% (16/27) metabolized by at least one enzyme having poor metabolizer (PM) genotype
- 38% (11/27) metabolized by CYP 2D6
- mainly drugs acting on CNS and cardiovascular systems, including _nortriptyline_

***Phillips et al, JAMA, 286 (18), 2001, 2270-2279***

## How Can PGt Improve Existing Therapies?

- All medicines that have been approved by the FDA for prevention or treatment of any disease in humans, under patent or not.

## 6MP:  Approved for Acute Lymphocytic Leukemia

**Mainstay of therapy for over 50 years**
**Clinical studies during last 20 years have focused on methods of refining optimal doses**
- incremental advances in using pharmacogenetics
**Risk of myelosuppression is primary limitation**
- chief determinant is dose, duration and intensity of treatment
- blood counts traditionally used to monitor therapy
- pharmacogenetic testing can significantly reduce, although not eliminate, this risk

## Off-Label Uses of 6MP

**Inflammatory bowel disease**
**Autoimmune diseases**
- rheumatoid arthritis
- ulcerative colitis
- psoriatic arthritis
- multiple sclerosis

## Genetic Basis for 6MP Intolerance is Well-Known*

**TPMT catalyzes inactivation of 6MP**
**TPMT-deficient patients accumulate excessive thioguanine nucleotides in hematopoietic tissues**
**Accumulation of thioguanine in RBC’s leads to increased risk of severe and possibly fatal myelosuppression**

** Causality well-established*

## Prevalence of TPMT Genotypes

- Three major SNPs (single gene) define mutant alleles (v)
-  Common: TPMT *3A (85%), TPMT *3C (<5%), TPMT *2 (<5%),
-  Rare: TPMT *3B (1:120,000)
-  Remaining allele:  TPMT*3D, but also contains TPMT*3A SNP

## Clinical Utility: Incidence of Toxicity

***Clinical Utility: Incidence of Toxicity***

-  Interrupting therapy for recovery from toxicity lessened intensity of treatment
-  Reduction of 6MP dose allowed for full dosages of other chemotherapy
-  TPMT polymorphism is important even for heterozygous patients

*Relling et al, J Natl Cancer Inst 1999;91:1983-1985*

## Clinical Utility: 6-MP Tolerability

***Clinical Utility: 6-MP Tolerability***

*Personal Communication, Dr. Atik Rahman*

## Would a TPMT Test Bring Value to Public Health:  Public Health Criteria for an “At-Risk” Genetic Test

**Phenotype is relatively common**
**Impact of phenotype is serious**
**Early detection alters treatment**
**Treatment alters outcome**
**Accurate, reliable test is available**
**Counseling is available**

*Secretary’s *Advisory Committee on Genetic Testing (SACGT), January 2000

## FDA Pharmacogenomics Working Group

**Lawrence Lesko (Chair), Office of Clinical Pharmacol. and Biopharm., CDER**
**Shiew-Mei Huang, Office of Clinical Pharmacol. and Biopharm/, CDER**
**Jerry Collins, Laboratory of Clinical Pharmacology, CDER**
**John Leighton, Office of New Drug, CDER**
**Robert Meyer, Office of New Drug, CDER**
**Richard Pazdur, Office of New Drug, CDER**
**Frank Sistare, Office of Pharmaceutical Science, CDER**
**Sue Jane Wang, Office of Pharmaceutical Science, CDER**
**Grant Williams, Office of New Drug, CDER**
**Mitchell Weitzman, ORP/DRPI, CDER**
**Mark Kramer, OC/ALS**
**Patricia Y. Love,  OC/ALS (On Detail)**
**David Essayan, Office of Testing and Research,, CBER**
**Joe Hackett, Office of Testing and Research, CDRH**
**Elizabeth Mansfield, Office of Testing and Research, CDRH**
**Jim MacGregor, Washington Operations, NCTR**

## Goals of FDA PG WG

**To serve on organizing committees for public workshops with industry**
**To make presentations at public meetings on regulatory perspectives**
**To develop a draft guidance for industry on pharmacogenomics**
**To discuss the scientific details of a “submission requirement” for PG data**

## Modern Rendition of Paracelsus

**Paracelsus**
**(1493-1541)**

**“****The dose makes the poison, ****but differently for genetically different individuals****.”**