Are You Ready for Pharmacogenomics?

Bruce Matthias

June 3, 2010

MUSE International Conference

Definition

Tailoring drug therapy to individual patients based on their own unique molecular characteristics such as individual differences in drug metabolizing enzymes, drug transporter activity, receptor sensitivity, etc. (genetic profile)

Background

• 1956 – Kalow – patients were identified that did not exhibit a typical response ot succinylcholine due to a genetic “variation”

• 1956 – Carson – excess hemolysis opbserved in “primaquine-sensitive” individuals

• 1959 – Evans – detailed “slow inactivators” and “rapid inactivators” of isoniazid

• 1959 – Fredrich Vogel – uses term “pharmacogenetics”

• 2003 – Human Genome Published

Single Nucleotide Polymorphisms (SNP’s)

• Human genome contains between 30,000 and 40,000 distinct genes.

• Genetic variation most commonly occurs as random variations between the nucleotide sequences of different individuals

• Single base-pair substitutions that occur with a frequency of greater than or equal to 1% in a population are referred to as single nucleotide polymorphisms (SNP’s)

• To date 1.4 million SNP’s have been identified• More than 60,000 occur in the coding regions of

proteins• Genes that code for the CYP enzymes 2A6, 2C9,

2C19, 2D6 and 3A4 have shown to be polymorphic with functional variations on a significant percentage of ethnic groups.

• The most common and best studied polymorphisms to date are those that affect drug pharmacokinetics and pharamcodynamics

Variability in Drug Response

• Pharmacokinetics– Absorption– Distribution– Metabolism– Excretion

• Pharmacodynamics– Drug target response

CYP2D6 - CYP2C19• CYP2D6 is involved in the metabolism of:

– Codeine (pro-drug)– Prozac– Zoloft– Paxil– Effexor– Hydrocodone– Amitriptyline– Claritin– Cyclobenzaprine– Tagamet– Tamoxifen (pro-drug)

• CYP2C19 is associated with the metabolism of:– Carisoprodol– Diazepam– Dilantin– Premarin– Prevacid– Plavix

By analyzing the variation in the two genes, the test predicts whether an individual will metabolize these drugs more quickly or more slowly than average. These variations can help the physician identify how a patient's metabolism works. If the test reveals that a patient metabolize drugs rapidly or slowly, the doctor may consider adjusting your drug dosages or switching to a non 2D6 or 2C19 metabolized drug. This information can help to maximize the likelihood of therapeutic effectiveness and minimize the risk of adverse drug reactions.

AmpliChip CYP450

• The first CYP2D6 and CYP2C19 genotyping test with FDA clearance.

• The AmpliChip CYP450 Test has greater than 99% accuracy for detection and genotype call rate.

• Covers clinically relevant polymorphisms known to impact drug metabolism.

• With its broad coverage of 27 alleles for CYP2D6 and three alleles for CYP2C19, the AmpliChip CYP450 Test is relevant for racially diverse populations.

AmpliChip CYP450 Results

Using a simple blood test, analysis of the data can be accomplished in eight hours:

The majority of people are extensive metabolizers (normal) who can be administered drugs following standard dosing practices.

Some people are poor metabolizers with a deficiency in drug metabolism, which could lead to life-threatening drug accumulation and severe adverse reactions.

Some people are intermediate metabolizers, meaning that they metabolize drugs at a slower-than-normal rate—somewhere between the rates of poor and extensive metabolizers.

Ultra-rapid metabolizers are those who break down drugs at faster rates than extensive metabolizers. These people may experience either no effect or less-than-expected effectiveness from their drug therapy. In the case of pro-drugs, the opposite phenomenon would occur.

Clopidogrel (Plavix) DNA Test - CYP2C19

Several recent landmark studies have proven the importance of 2C19 genotyping in treatment using clopidogrel or Plavix. Researchers have found that patients with variations in a gene called cytochrome P-450 2C19 (CYP2C19) have a 3.58 times greater risk for major adverse cardiovascular events such as death, heart attack, and stroke; the risk was greatest in CYP2C19 poor metabolizers. The abstract is available in the online verison of the New England Journal of Medicine.

Population Frequency of Cytochrome P450 (CYP) 2C19 Metabolizer Types

• There is wide variability among populations. People of Asian and African ancestry have a greatly increased prevalence of poor metabolizer status.

• CYP2C19 is not just involved in the metabolism of clopidogrel, it metabolizes many other medications including antidepressants, barbituates, proton pump inhibitors, antimalarial and antitumor drugs.

Who Should Be Tested

• The CYP2C19 test for clopidogrel or Plavix is considered appropriate for any patient taking or considering this medication.

• The process is simple. You can order testing directly if you have a physician prescription or your healthcare provider can request testing for you.

Warfarin Sensitivity (CYP2C9 & VKORC1 )

• Warfarin overdosing can result in life-threatening

• Up to 1 percent mortality and 15 percent morbidity due to bleeding complications.

• Mutations in the CYP2C9 and VKORC1 genes. The common CYP2C9 gene mutations (*2 and *3) with the VKORC1 gene promoter mutation (c.-1639G>A), are estimated to account for 40-63 percent of the variability in therapeutic warfarin dose.

• VKORC1 stands for Vitamin K epoxide reductase, complex 1 gene.

Warfarin inhibits the product of this gene (VKOR), a key enzyme in the vitamin K cycle

• Methylates anticancer drugs such as mercaptopurine and

azathioprine• Several SNP’s have been identified for TMPT which can

alter its activity of methylation that is involved in both activation and metabolism of mercaptopurine

• Altered enzyme activity will affect the concentration of both active and toxic metabolites

• NTI – life threatening myelosuppresion is a major concern

TPMTThioPrine MethylTransferase

NAT2N-AcetylTranferase 2

• Involved in the metabolism of several agents (hydralazine, isoniazid, procainamide, dapsone)

• Has multiple phenotypes – Fast/rapid– Intermediate– Slow

• Recognition of variation dates back to 1960’s prior to the idea of the NAT2 enzyme or the idea of genotyping

FDA

• As a result of demonstrated clinical impact of polymorpisms in the CYP2C9 and TMPT, the FDA recommends that patients be tested for the presence of the variants before receiving warfarin or azathioprine

• The FDA currently suggests that NAT2 genotyping may be useful in tuberculosis patients being treated with a combination of rifampin, isoniazid, and pyrazinamide

• Poor 1A2 metabolizers are a risk of

several potentially fatal toxicities including agranulocytosis, seizures and myocarditis

• Patients with higher-than-normal 1A2 activity are at increased risk of treatment failures

CYP1A2 Controls the Clearance of Clozapine

UGT1A1UDP-GlucuronosylTranferases

• Patients that are homozygous for the UGT1A1*28 allele have impaired metabolism of the active form (SN-38) of the anticancer agent irinotecan that can result in severe, dose-limiting toxicity (diarrhea, neutropenia).

• The FDA currently recommends an assessment of a patient’s level of UGT1A1 activity prior to the initiation of irinotecan therapy

Pharmacogenomic Data extracted from FDB

GNNDDXCN_DRUG_DES

C DXID_DESC100 DDXCN_REF

COLCHICINE/PROBENECID

COLCHICINE

Hemolytic Anemia from Pyruvate Kinase and G6PD Deficiencies WWW.G6PD.ORG

DICUMAROL

COUMARIN ANTICOAG.

Bleeding Risk Associated with Vitamin-K-Epoxide Reductase (Warfarin-Sensitive) Gene MEDWATCH 08/17/07

COLCHICINE/PROBENECID

COLCHICINE

Hemolytic Anemia from Pyruvate Kinase and G6PD Deficiencies WWW.G6PD.ORG

WARFARIN SODIUM

COUMARIN ANTICOAG.

Bleeding Risk Associated with Vitamin-K-Epoxide Reductase (Warfarin-Sensitive) Gene MEDWATCH 08/17/07

ISONIAZID

ISONIAZID

Slow Acetylator due to N-acetyltransferase Enzyme Variant ISONIAZID PI, 10/01 (WEST)

ABACAVIR SULFATE

ABACAVIR

HLA-B 5701 Positive Status ZIAGEN PI, 07/08

WARFARIN SODIUM

COUMARIN ANTICOAG.

Poor Metabolizer due to Cytochrome p450 CYP2C9 Variant MEDWATCH 08/17/07

ABACAVIR SULFATE

ABACAVIR

HLA-B 5701 Positive Status ZIAGEN PI, 07/08

CARBAMAZEPINE

CARBAMAZEPINE

HLA-B 1502 Positive Status MEDWATCH 12/12/07

REDUCING ADRS AND SAVING MONEY

More than 50% of Americans have gene based variations that can be tested for and that increase the risk of an ADR.

The wide use of DNA Drug Sensitivity Testing has the potential to save tens of thousands of lives, prevent hundreds of thousands of serious events that initiate or extend hospital stays, and save hundreds of millions of dollars in health care costs. Fifty-nine percent of drugs most commonly cited in ADR studies are processed by enzymes with genes known to have poor metabolizer variants. This is compared to 7% of a random selection of the top selling drugs. (JAMA 286:2270 2001).

Currently available tests help predict a patient's response to many prescription, OTC (over-the-counter) and herbal medicines including those used to treat depression, anxiety, seizures and psychoses; blood pressure, anticoagulation and other heart medicines; anti-diabetic agents, and many pain relievers.

Many known drug drug interactions are based on a knowledge of the drug metabolizing systems that have a high level of genetic variation. When those variations are present in individuals taking more than one drug the chance of having an adverse drug reaction is greatly increased.

Hospitalized psychiatric patients who are poor metabolizers cost $4,000 - $6,000 more in medical care compared to patients with an average metabolizer genotype. ALL antidepressants and antipsychotics are processed by enzymes with a high incidence of poor metabolizers. Journal of Clinical Psycopharmacology 20:246 2000

Review – What We Know

• We know that genetic differences can affect drug response in patients

• We have identified specific SNP’s that produce specific responses

• We can now identify patients that have specific Genotypes

• Where do we go from here?

Ideal (future) Genetic Profile• Integrated within EMR (Inpatient and

Ambulatory)• Demo recalled• Audit trail• Accessible to all caregivers• Integrated with PHA and POM to provide

Clinical Decision Support• Database updated by other vendor

supplier

Prototype (current) Genetic Profile Options

• Integrate within PHA Patient Data Screen• Demo recall on Pharmacy Profile• Audit trail (basic)• Access based on PHA module access• Clinical Decision Support can be Integrated

with PHA and POM by utilizing RULES• Database updated manually based on

literature review

Current State

• Currently No Genetic Profile Application /Routines in MEDITECH or LSS

• Limited data available from Formulary service or Other Vendors

• No Pharamcogenomic data incorporated into Other Vendor Order Sets

Customer Defined Screen

• Query Types – Group response• Single query multiple response vs Multiple

Queries with single response• Single Query easier to maintain but allows

inappropriate selections.• Multiple queries require additional query

build and screen modifications for added genetic traits

Prototype (sample) Genetic Profile

WarfarinDosing.com - Profile

Clinical Decision Support - Rules

• Suggest ordering appropriate Genetic Screening – if not already on Genetic Profile (Include reason for testing )

• Review Genetic Profile and warn user regarding potential adverse effects (i.e. Warfarin – bleeding)

• Suggest alternate therapy when appropriate (i.e. Effient vs Palvix or H2 antagonist vs PPI)

Pharmacogenomic Rules may meet the “rules” requirement for “Meaningful Use”

Other Clinical Decision Support

• Black box warnings include PGEN recommendations

• Use Free text headers and reminders to instruct evidence based PGEN practice

• Use POM Imbedded links to facilitate reference availability as well as functional PGEN dosing sites

Dosing Algorithms

• PGEN dosing algorithms are very complex and must take a number of factors into consideration

• Currently several vendors are offering dosing software that utilizes PGEN data

• Future integration will be key to provide accurate patient dosing

Resources

• www.GeneMedRx.com• www.warfarindosing.org

IMBEDDED LINKS

OE Order Set Dictionary – Headers/Reminders

Adding a Link

Remember Lab

Be sure to coordinate efforts for Pharmacogenetic testing with your Lab Department. It will be important for the physicians to be able to order the tests as recommended in the evidence

Conclusion

As more patients have genetic profiles performed and more information is available about medications and their interactions with different genetic profiles, we will be able to tailor a regimen with specific medications and doses for the patient based on the patient’s genetic make-up. This customization will be in addition to other commonly acceptable variables used today (age, weight, sex). The Hippocratic Oath states first do no harm. With genetic testing, many of the worst side effects from medications may be more predictable and can prevent patient deaths from occuring.

QUIZ

Name each of the following terms|1. SNP

2. VKORC1

3. NAT2

4. TMPT

5. UGT1A1

Questions?

Bruce.matthias@theingroup.com