Interpatient Variability of Drug Response.

Genetic Factors

Pharmacogenetics

PGx chapter:

Website: http://www.pharmgkb.org/

Pharmacogenomics tutorialshttps://preview.pharmgkb.org/resources/education/tutorials.jsp

PHARMACOGENETICS

• The study of how genes affect the way people respond to drugs. Includes examining genetic variation on drug disposition, toxicity and efficacy. Single gene-drug interaction.

PHARMACOGENOMICS

• The study of the role of genes & genetic variations in the molecular basis of disease & resulting pharmacological treatment of disease. Full set of PK/PD genes examined. More complex interactions.

P- etics vs P-omics

DNA- Instruction Manual for the Body

DNA strands are in a specific sequence of base pairs DNA strands are in a specific sequence of base pairs (a 4-letter alphabet) to make words (genes). (a 4-letter alphabet) to make words (genes).

GENE mRNA PROTEINGenes are responsible for “inherited or genetic traits

The order in which the bases are arranged is The order in which the bases are arranged is how DNA information is transmitted to how DNA information is transmitted to your bodyyour body

Just like the order of the letters in a sentence, the sequence of the DNA bases spells out instructions When the letters are in the wrong deror or if letters are skpped, the sentence may not make sense to the body. This results in genetic defects in the protein the gene is responsible for making.

Genetic Variability• Variations in genetic sequences frequently occur between individuals.• Most common is a single nucleotide polymorphism within gene (SNP). • If body is not able to “read”DNA code- may result in abnormal proteins and loss in function.

gactaagtcggTTaactg… gactaagtcggCCaactg …

*10 million putative SNP locations in human genome

Classical PGx: Genetic Classical PGx: Genetic Variation in Drug Variation in Drug

Metabolizing EnzymeMetabolizing Enzyme

Persons with SNP genetic defect in enzyme resulting in poor

metabolism of drug

Build up of drug in blood and tissues

Altered Drug Response:

Toxicity after Standard Doses

Metabolizing Enzyme

• For this course we will primarily discuss single genetic traits affect drug disposition and efficacy (Pharmacogenetics)

• Functional polymorphic differences have been discovered for numerous genes which affect the PK and effects of drugs. Includes genetic polymorphisms of : – Drug metabolizing enzymes– Drug transporters– Drug receptors

• Most polymorphs associated with reduced activity of the protein.

• Associated with increased incidence of toxicity or therapeutic failure in patient population.

• Polymorphisms differ in frequency among ethnic and racial groups.

Other terms

Allele: one of alternative genetic variants on a single chromosome. A human has two chromosomes, which may carry the same or two different alleles.

Genotype: The specific genetic variants at one or more loci of an individual.

Phenotype: Physical trait or characteristic associated with genotype. eg. Enyzme function

Polymorphisms: Genetic variations with a frequency of >1% of the population. Gene products exhibit altered activity in relation to normal (wild type).

Single Nucleotide Polymorphism (SNP)- substitution of a single nucleotide base.

History of PGx

1950/60s

• Glucose-6-phosphate-dehydrogenase

– Severe anemia in some African-Americans upon taking primaquine, later found in 400 million Africans.

• Isoniazid for tuberculosis

– Slow and rapid metabolizers, related to N-acetyltransferase variants.

• Unusually long anesethesia with succinylcholine

– Prolonged effects due to atypical cholinesterase

Classical Pharmacogenetics - An observation of abnormal drug response

1960-70s

• Discovery that response to debrisoquine (blood pressure medicine) and opioids was related to the level of CYP450 activity

• Later found to be CYP2D6, with many (>80) polymorphisms in human population

1970s:

• Analysis of clinical phenotypes related to known genes

– E.g. hemoglobinopathies leading to sickle cell anemia, thallesemia, clotting disorders

Genetic Variantsof Drug Metabolism

Cytochromes P450Cytochromes P450CYP2C9CYP2C9CYP2D6CYP2D6CYP2C19CYP2C19

AcetyltransferasesAcetyltransferasesNAT2NAT2

MethyltransferasesMethyltransferasesTPMTTPMT

DehydrogenasesDehydrogenasesDPDDPDALDHALDH

SulfotransferasesSulfotransferasesSULT1A1SULT1A1

Polymorphic GenesPolymorphic Geneswith Identified SNPs with Identified SNPs

Involved in metabolism of 25% of all therapeutic drugs (50 of top 100): – dextromethorphan– opioid analgesics

- codeine, hydrocodone...

– antidepressants - SSRI

- tricyclic antidressants

– cardiac drugs- -blockers

- debrisoquine

• Most recognized and characterized

polymorphism. • Clinical consequences can be devastating.

1) CYP 2D6

Prozac- Related Death of 9 Prozac- Related Death of 9 Year Old Boy : Micheal Adams- Year Old Boy : Micheal Adams-

ConroyConroy

Initially thought to be an intentional drug Initially thought to be an intentional drug overdose,overdose,

parents were charged with murder. parents were charged with murder.

• 22ndnd Medical examination found that boy Medical examination found that boy had a had a genetic defect genetic defect with thewith the CYP2D6 CYP2D6 drug metabolizing enzymedrug metabolizing enzyme..

• Genetic defect resulted in poor Genetic defect resulted in poor metabolism of Prozac resulting in a toxic metabolism of Prozac resulting in a toxic build up of his prescribed Prozac build up of his prescribed Prozac dose…. eventually death.dose…. eventually death.

1999

Gene transforms drug into morphine- kills infant of

nursing mother• Newborn infant dies. While initially believed

to be SIDS, autopsy indicated death occurred due to Morphine overdose.

• Nursing mother was prescribed routine doses of codeine analgesic for episiotomy pain. Codeine products are listed as compatible with breast feeding.

• While codeine is normally converted to numerous metabolites, Mother was found to carry multiple genes of CYP2D6, which specifically transforms codeine into morphine. Abnormal, toxic levels of morphine were found in breast milk.

May, 2006 Toronto Globe & Mail

• Four phenotypes: Poor (PM): two non functional alleles

Intermediate (IM): two fxn or 1 null & 1 fxn

Extensive (EM): at least 1 fully functional gene

Ultrarapid (UM): gene duplication

• PM frequency in North American: (overall 5-10%)– different frequency according to ethnicity

• UM frequency (CYP2D6*2xn)– Ethiopians: 16% – Saudi Arabian: 10.4%– Spaniards: 3.5% – Tanzanian: 3.0%– Caucasian- North American: 1-5%– Asian (Japanese & Chinese) : 1-2%

CYP 2D6 Polymorphisms

CYP2D6 Phenotypes

2D6 Enzyme ActivityHigh to

Low

Frequency in Population

CYP2D6 Genotypes

More than one SNP or allele associated with altered enzyme function.

*2 in > 25% CA & AA (normal enzyme activity)* 4 in 20% CA <10% AA (no enzyme activity)*10 in > 70% Asians ( enzyme activity)

*4, *5 – no enzyme*10,*17 - enzyme

Examples of drugs metabolized by the cytochrome P450 CYP2D6 enzyme

Tricyclic antidepressants

Amitriptyline Clomipramine Desipramine

Imipramine Maprotiline Nortriptyline

SSRI and atypical antidepressants

Fluvoxamine Fluoxetine Paroxetine

Mianserin Sertraline Venlafaxine

Antipsychotics

Clozapine Haloperidol Chlorpromazine

Olanzepine Perphenazine Risperidone

Opioid Analgesics

Codeine Dextromethorphan Ethylmorphine

Hydrocodone Oxycodone Tramadol

Antiarrhythmics/ -blockers

Amiodarone Flecainide Mexiletine

Proprafenone Carvedilol Timolol

Antiemetics

DolasetronMetoclopramide Ondansetron

Anticancer

Doxorubicin Lomustine Tamoxifen

The Oncologist. Interethnic Differences in Genetic Polymorphismsof CYP2D6 in the U.S. Population: Clinical ImplicationsS. Bernard, K. Neville, A. Nguyen, D. A. Flockhart

Clinical finding in PM:• Lack of efficacy of opioid pro-drug products

– Codeine, tramadol, hydrocodone: efficacy primarily due to active morphine ( or morphine based metabolite) which is formed by CYP2D6.

– Reduced analgesia in PM

• High incidence of adverse effects with CYP2D6 substrates, altered dose requirements; rare serious adverse reactions seen. – Estimated that an ADR occurs in every

PM dosed with drug relying on CYP2D6 metabolism

CYP 2D6 PM

Altered Toxicity:

Clinical Report: 62 yr Male: codeine tid for cough. Loss of

consciousness on Day 4 (12 hr after last dose).

• ICU ventilation, miotic pupils, Glasgow coma score 6.

• Morphine blood level 80 g/L (1- 4 g/L).• Naloxone administered: awakened patient• Genotype: > 3 functional 2D6 alleles

Altered Efficacy:

Therapeutic failure of Antidepressants

CYP 2D6 UMUltrametabolizers

Aus R. Weinshilboum: Inheritance and drug response, New England Journal of Medicine 348, 529-537 (2003)

CYP2D6 Polymorphisms and Nortriptyline PK

PMIMEMUMUM

A woman was hospitalized for gastrointestinal bleeding. Although she had been receiving only warfarin 5 mg/day, her international normalized ratio (INR) was 66. Warfarin was discontinued, and her INR fell to 3.7 after transfusion of fresh-frozen plasma. However, it rose again spontaneously to 7.5. Eleven days after the last dose of warfarin had been administered, it was still detectable in the patient's plasma...

Bloch et al., Pharmacotherapy 22: 97-101, 2002

** Subsequent genotyping demonstrated CYP2C9 SNP varient in patient

2) CYP 2C9

Polymorphic CYP2C9 and Warfarin Sensitivity Warfarin Warfarin

• AnticoagulantAnticoagulant

• Metabolized by CYP2C9Metabolized by CYP2C9

• Patients treated to effectPatients treated to effect

- - Under-anticoagulation- thrombosisUnder-anticoagulation- thrombosis

- - Over-anticoagulation-bleedingOver-anticoagulation-bleeding

• 50-fold variation in required 50-fold variation in required

dosedose

• CYP2C9*3CYP2C9*3 allele SNP (Ile allele SNP (Ile359359Leu) Leu)

results in 95% loss ofresults in 95% loss of enzyme enzyme

functionfunction

• Homozygotes for CYP2C9*3 Homozygotes for CYP2C9*3

require drastic reduction of require drastic reduction of

warfarin dosewarfarin dose

Polymorphic CYP2C9 and Phenytoin toxicity

Kidd et al., Pharmacogenetics 11: 803, 2001

The study subject was a female African–American presented to the emergency department with phenytoin toxicity evidenced by mental confusion, slurred speech, memory loss and the inability to stand. She exhibited extremely poor clearance of phenytoin with an elimination half-life of 13 days.

Genotyping demonstratedCYP2C9varient in patient

CYP2C9 PolymorphismsPM: *2 and *3 varients

Frequency of Polymorphisms: 14-28% Heterozygotes (1*/3*)

Drug Clearances 40-70%

0.2-1% Homozygotes (3*/3*)Drug clearances < 25%

Drugs Metabolized by CYP2C9S-Warfarin

NSAIDs / COX-2 inhibitors: Celecoxib, Naproxen, Piroxicam, Diclofenac

Oral hypoglycemics:Tolbutamide, Glipizide, Glyburide

Sulfonylureas: Phenytoin, Tamoxifen, Floxetine,

Fluvastatin

3) CYP2C19Originally identified as S-mephenytoin hydroxylation polymorphism.

Numerous drugs metabolized by 2C19 Proton Pump Inhibitors: omeprazole

Anti-epileptics: diazepam, phenytoin, S- mephenytoin, phenobarbitone

Tricyclic Antidepressants: amitriptyline, imipramine

WarfarinNelfinavir

Poor Metabolizers: Polymorphisms:

CYP2C19*2 & CYP2C19*3

Ethnic Differences3-6% Whites13-23% Asians

CYP2C19 PM Distribution in Ethnic Groups.

ASIAN 15%

Caucasian 3%

Clinical outcomes:Effect of CYP2C19 genotype on H. pylori

infection cure rate after ulcer therapy with omeprazole and amoxicillin

0

10

20

30

40

50

60

70

80

90

100

wild-type hetero mutant

gastricduodenal

Takahisa et al., Ann Int Med 129: 1027-1030, 1998Takahisa et al., Ann Int Med 129: 1027-1030, 1998

In

fecti

on

cu

re r

ate

(%

)

• Mutant (genetic varients) PMs have 6x higher AUC of Omeprazole than wild-type. • Mutant and hetero have longer duration of acid suppression.• Require higher doses in wild-types?

4) N- Acetyltransferase

• Involved in the acetylation of several drugs:

– Caffeine, isoniazid, procainamide, hydralazine, sulfamethazine, dapsone

• Rapid and slow acetylatorsEskimos & Asians: 100% rapidEgyptians : 20-40% rapidNorth American (all races): 50% rapid

Clinical Impact:Rapid Metabolizers

hepatotoxicity with isoniazid

Slow Metabolizers– Serious adverse reactions

• Lupus reactions (hydralazine, procainamide)

• Peripheral neuropathies (isoniazid)

5) Thiopurine methyltransferase

(TPMT)• Metabolizes 6-mercaptopurine,

azathioprine 6-MP is used in the treatment of 6-MP is used in the treatment of

childhood leukemia.childhood leukemia.• Incidence of decreased activity: 11%• Incidence of deficiency: 0.3%

• Deficiency: profound bone marrow depression

Example:Example:6-MP toxicity in TPMT 6-MP toxicity in TPMT genotypes genotypes

0

20

40

60

80

100

wild-type hetero mutant

Incidence of ToxicityIncidence of Toxicity

•

- - Children deficient in TPMT show marked 6-MP Children deficient in TPMT show marked 6-MP toxicitytoxicity- Children with very high TPMT have therapeutic - Children with very high TPMT have therapeutic failurefailure

Mayo Clinic and St. Jude Children’s Mayo Clinic and St. Jude Children’s Hospital now use prescreening tests for Hospital now use prescreening tests for

TPMT variants to set 6-MP dose levels in TPMT variants to set 6-MP dose levels in the treatment of childhood leukemiathe treatment of childhood leukemia

6. Cytochrome P450 3A

• CYP3A4 / CYP3A5 responsible for metabolism of approx 50-60% of clinical used drugs.

• Account for 30% of hepatic CYP P450 content.

CYP3A4 polymorphism• Clinically important CYP3A4 genetic

variants have not yet been identified.

CYP3A5 polymorphism– CYP3A5*3 allele non-functional

• Incidence: 82 % in Caucasians, 6.5% in AA.

– CYP3A5*6 / *7 non-functional• Incidence predominate in AA population.

B) Drug Transporters

MDR1 (ABCB1)• Encodes for P-glycoprotein, an efflux

transporter• Involved in distribution/elimination of

many clinically important drugs. • Prevents or limits absorption of drugs

from GIT and entry of drugs into CNS.

• Incidence of genetic varients and impact on function not fully characterized.

• MDR1 polymorphisms associated with increased bioavailability of fexofenadine and increased efficacy of antiretroviral therapy in AIDS patients.

OATP1B1 (SLCO1B1)- Encodes for organic anion transporter - involved in cellular influx of endogenous &

exogenous anionic compounds.- HMG-CoA reductase inhibitors (statins), steroids,

thyroid hormones, arachidonic acid metabolites

- Polymorphisms (activity)- ↑ AUC of statins (pravastatin, atorvastatin,

rosuvastatin) due to hepatocellular uptake & clearance.

- AUC fexofenedine & repaglinide due to intestinal uptake.

C) Drug Receptors.

Examples:

1) 2-adrenergic receptor SNP varients– Frequency of polymorphism- 37% .– Associated with lung function in

asthmatic patients. response to 2-adrenergic agonist (ie.

Albuterol). • Polymorphisms explains up to 20% of

variable response.

2) ApoE4 genotype– Predictive of response to tacrine therapy

in Alzheimer’s disease.– Absence: 84% success rate– Presence: 40% success rate

Pharmacogenetic varients can be distinguished according to the number of genes responsible for the “phenotype”

• Most phenotypes identified to date (ie PM vs EM) are Monogenic (due to allelic mutations at a single gene locus) – Initial pharmacogenetic examples are simple,

with one gene-one drug.

– Has been hard to find consistent associations when examining a single SNP alone.

• Phenotypes based on variation of multiple genes (Polygenic) are now being examined.– Increasingly being used to explain sources of

patient variability in disease and therapy.

– Associations of complex drug response with genetic varients is where pharmacogenomics is heading over the next 5-10 years.

Non-classical Polymorphisms

1) Non-coding promoter variants– Influences basal expression or

induction of protein

UGT1A1*28 - Polymophism in TATA-box

promoterr region leads to expression of UGT1A1.

– UGT1A1*28 common in Caucasians

(10 - 40%) and is associated with a significant decrease in UGT1A1 activity.

Clinical implication:- Irinotecan: 4X ↑ in severe dose-

limiting toxicity in PM.

Ironotecan is activated to SN-38, which is

metabolized by UGT1A1

Ironotecan

SN-38G

SN-38

CYP3A4

esterase

UGT1A1

N N

O

O

NN

O

O

OH O

C2H 5

N

N

O

O

OH O

C2H5

H O

N

O

O

NN

O

O

OH OC2H5

HNH O

O

O

N

N

O

O

O

HO

C2H5

O

C O O H

O HHO

Diarrhea associated with decreased metabolism of SN-38 in patients

Gupta, Cancer Res, 1994

MJR040902

CPT-11

SN-38

SN-38G

NO DIARRHEA DIARRHEA

AUC Ratio7:1

AUC Ratio1:1

Active metabolite of SN-38 metabolized by UGT1A1

Variability in metabolism of SN-38 associated with toxicity

Clinical Study :Neutropenia correlated with UGT1A1 *28 7 genotypes in

patients

5/6 6/6 6/7 6/8 7/7 7/8

0

2500

5000

7500

UGT1A1 genotype

ANC

nadi

r (ce

lls/u

l)

Nonparametric trend analysis among 6/6, 6/7, 7/7, p<0.01

50% incidence

of Gr 4 neutropenia

No Gr 4 neutropenia

Wh

ite

blo

od

ce

ll c

ou

nts

Revised Irinotecan (Camptosar®) label (effective June 7th, 2005)

• Haplotypes – A combination of alleles (DNA

polymorphisms) which are located closely together on the same chromosome and tend to be inherited together.

• Combination of SNPs that are inherited in blocks. Can be on different genes

Eg. VKORC1 haplotype and warfarin (Vitamin K epoxide reductase complex)

- 10 common noncoding VKORC1 SNPs found with five major haplotypes.

– Haplotype A associated with low dose requirements.

– Haplotype B associated with high dose requirements.

Pathways

– Interactive effects of several genes in a pathway.

Example: • Recently found that warfarin doses can be

better predicted by combining genotype information for CYP2C9 (enzyme responsible for its metabolism) and haplotypes of its drug target, the Vitamin K epoxide reductase complex 1 (VKORC1).

• FDA recommends revisions in warfarin product label to include information about polymorphisms of both CYP2C9 and VKORC1

• Whole Genome Scans being used to find complex associations between genetic variation and response.

ResponderResponder Non-ResponderNon-Responder

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Treatment WeekTreatment Week Treatment WeekTreatment Week

Genome-wide association studies

Gene Expression Response to Cyclosporin and rhIL11 in Psoriasis

• Clinical Trial Clinical Trial Evaluated >7000 Evaluated >7000 genes in genes in microarraymicroarray

• 159 found to 159 found to associate with associate with psoriasispsoriasis

•142 found to 142 found to associate with associate with improvement improvement of psoriatic of psoriatic skin in skin in response to response to therapeutic therapeutic agentsagents

• Gene expression Gene expression reflects drug reflects drug responseresponse

Andrew J. Dorner Molecular Medicine, Wyeth

Self-organizing map analysis of drug Self-organizing map analysis of drug response for psoriasis-related genesresponse for psoriasis-related genes

Patient Individualization of Drug

Therapy based on Genetic Factors

• Virtually Nothing in Practice- Yet.– Genotyping is a relatively new area.– Few patients have information on their

genotype/phenotype.– Research findings have not translated

into distinct dosage recommendations for use in clinical practice.

– Primary strategy of Rx&D has been to avoid marketing new drugs with polymorphic characteristics.

• Advancement of methodologies and services to genotype patients

• Pharmacist’s role in developing drug/dosage strategies very important

Individualization of Doses in Patients with Genetic Varients

• Consider relative contribution of the polymorphic enzyme to the total elimination of the drug.– ie. What % of CLT is it responsible for?

• Consider therapeutic index of drug.

• Use logic

Example: SSRI drug cleared via CYP2D6 hepatic metabolism

(60%) and renal excretion (40%). CLT = 680 ml/min. IV dose of 5 mg/day gives therapeutic plasma Css of 5.1 g/L. – CYP2D6 enzyme responsible for 60% of total

drug clearance. [CLH = 408 ml/min]– CYP2D6 *3/*3 SNP varient results in non-

functional enzyme (0% activity, CLint = 0, CLH = 0].

CLT = CLR + CLH = 272 ml/min (16.3 L/hr)

Css = Dose / τ* CLT Dose / τ = Css * CLT

Dose = 5.1 g/L * 16.3 L/hr = 83.1 g/hr = 1.99 mg/day ~ 2.0 mg/day IV

Patients who are homozygotes for this non-functional SNP should receive 40% of normal IV dose.

What if we are giving an oral dose? How do we calculate the oral bioavailability and hepatic first pass metabolism in PM?

What if SNP mutation results in enzyme with 50% function or if have one functional and one non-functional gene (IM)? (ie. Enzyme activity = 50%).

Will work on these types of dosage adjustment calculations after we finish up lectures on dosage adjustment based on variable hepatic function.

Clinically used Dosage modifications

Based on PK principles, dosage guidelines for antidepressant drugs were recommended for CYP2D6 and CYP2C19 Genotypes. (Acta

Psychiatr Scand 2001; 104:173-92) Dose change based on:

– Significant involvement of 2D6 or 2C19 in metabolism of drug.

– Clinical reports of significant changes to Css & AUC in PM vs EM

– Evidence of adverse events

– Evidence of therapeutic failure

Dosage Adjustment Calculations

• PK changes based on clinical reports in liter. Review of AUC or Css in EM, IM & PM

n= AUCEM / AUCPM

m = AUCEM /AUCIM

• Genotype doses then calculated based on the assumption that standard dose (DAv) recom. are based on studies in genetically mixed populations. DAv

considered as weighted mean of Caucasian population. – CYP2D6 based on genotype frequency of: 10%

PM, 40% IM and 50% EM.

DEM (%)= ______100__________

( 0.1*n + 0.4*m + 0.5)

DPM (%) = n * DEM

DIM (%) = m * DEM

Dosage Guidelines

% Manufacturer’s Recommended Dose(+++: no dosage adjustment necessary)

CYP 2D6 Phenotype CYP 2C19 PhenotypeDRUG

PM EM PM EM

Amitriptyline 50% 120% 60% 110%Citalopram +++ +++ 60% +++

Clomipramine 60% 120% 70% +++DesimpramineNon-linear PK

30% 130% EM260% UM

+++ +++

Fluoxetine 70% 110% +++ +++Fluvoxamine 60% 120% +++ +++Imipramine 30% 130% 60% +++Maprotiline 40% 130% +++ +++Mianserine 70% 110% EM

300% UM+++ +++

MoclobemideNon-linear PK

+++ +++ 40% 1st

60% MD110%

Nortriptyline 50% 120% EM230% UM

+++ +++

Paroxetine 20% 1st

70% MD130% 1st

110% MD+++ +++

Trimipramine ??? ??? 40% 110%Venlafaxine 20% 130% ??? ???

-Not ideal but 1st guidelines developed & made publically available.

Nomogram of dose estimates of

antidepressants based on CYP2C19 Genotype

Recently found on Genelex® website-PM : require 40-70% of most of the antidepressants

IM: require 70-85%

Nomogram of dose estimates of

antidepressants based on CYP2D6 Genotype

Recently found on Genelex® website.

PM : require 20-70% of most of the antidepressants

IM: require 75-85%

UM: require 100-200%

Netherlands: Royal Dutch Assoc. for

Advancement of Pharmacy• Established Pharmacogenetics Working Group

in 2005. – 15 multidisciplinary “clinical” working group

– Objective to develop PGx based dose guidelines (based on literature review) & integrate recommendations into automated computer medication prescribing/ surveillance programs.

1st recommendations released October 2006- Examined 85 genotype/phenotype-drug comprising 26 drugs. Assessed drugs were primarily substrates of CYP2D6 (21/26).

- Therapeutic (dose) recommendations compiled for 17 of 26 assessed drugs.

Calculation of Dose Adjustments

• PK changes based on clinical reports in literature. Review of AUC, Css or oral CL in EM, IM & PM

• Assumed that currently used standard doses are representative for EM.

• Calculated dose adjustment for each geno/phenotype based on each report using:

DPM (%) = [AUCEM / AUCPM ] *100 %

- Average mean of results used in final dose adjustment recommendation.

Swen J et al. CPT, 2008 (PHM324 website) DO NOT DISTRIBUTE will not be published until June 2008.

Pharmacist’s Role1) Interpretation of information

– When is it clinically relevant ?• Recognize polymorphisms which

predisposes patients to toxic plasma conc, toxic effects or are assoc. with inefficacy (nonresponders).

– Assistance in Appropriate Prescribing

2) Patient Education

3) Assistance in Establishing Drug and Dosage “Guidelines” for Genotype Populations.– Think about how you could estimate and

advise physicians on dosage changes in patients with abnormal genotypes when no published dosage recommendation are available

• Unless “something can be done” from the information obtained from the genetic tests, there will be little clinical value in the tests.

• Intervention by pharmacists – ‘drug experts’ who are trained in pharmacogenomics, pharmacokinetics and individualization of drug therapy - will be critical.

Data Sourceshttps://preview.pharmgkb.org/index.jsp

CYP P450 substrates:http://medicine.iupui.edu.flockhart/

What will be the driving force for pharmacogenetic testing?

Test prices start at $ 199Test prices start at $ 199..

Direct to consumer marketing of genetic testing (for disease risk and pharmacogenetics) has begun. Many are reaching consumers through the internet.

Direct-to-Consumer Genetic Testing

Gender/Sex

• Hormone effects– affects fat distribution/ ratio– altered drug metabolism ?

– Oral contraceptives- CYP3A activity

Dextromethorphan Metabolite Ratios

in women at different stages of the

menstrual cycle.MenstrualPhase

FollicularLutealMensesOvulatory

MetaboliteDX:DM

400200130169

RatioDM:3MM

2.661.512.713.73

• CYP activity dependent on Menstrual Phase.