Date post: | 10-Apr-2018 |
Category: |
Documents |
Upload: | tushar-pareek |
View: | 227 times |
Download: | 0 times |
of 58
8/8/2019 Pharmacogenetics 2008 for Med Students
1/58
Pharmacogenomics:Pharmacogenomics:
designer drugsdesigner drugs
Paula Gregory, Ph.D.Paula Gregory, Ph.D.
Dept. of GeneticsDept. of Genetics
8/8/2019 Pharmacogenetics 2008 for Med Students
2/58
Ifit were notfor the great variability amongIfit were notfor the great variability among
individuals, medicine might as well be aindividuals, medicine might as well be a
science and not an art. Sir William Oslerscience and not an art. Sir William Osler
8/8/2019 Pharmacogenetics 2008 for Med Students
3/58
Did you know?Did you know? Over 2 million people are hospitalized eachOver 2 million people are hospitalized each
year for adverse reactions to prescriptionyear for adverse reactions to prescription
drugs.drugs.
Every year more than 100,000 people dieEvery year more than 100,000 people die
from those reactions, making it the sixthfrom those reactions, making it the sixth
leading cause of death!leading cause of death!
8/8/2019 Pharmacogenetics 2008 for Med Students
4/58
PharmacogenomicsPharmacogenomics
Will allow:Will allow:
individualized medication useindividualized medication usebased on geneticallybased on genetically
determined variation in effectsdetermined variation in effects
and side effectsand side effects
use of medications otherwiseuse of medications otherwiserejected because of side effectsrejected because of side effects
new medications for specificnew medications for specific
genotypic disease subtypesgenotypic disease subtypes
8/8/2019 Pharmacogenetics 2008 for Med Students
5/58
How Pharmacogenomics works
How Pharmacogenomics works
Identifying gene sequenceIdentifying gene sequence
variations (SNPs) that affectvariations (SNPs) that affect
drug responsedrug response
Identifying diseaseIdentifying disease
susceptibility genes whichsusceptibility genes which
represent potential newrepresent potential new
drug targetsdrug targets
Identifying gene sequenceIdentifying gene sequence
variations that can causevariations that can cause
adverse drug reactionsadverse drug reactions
8/8/2019 Pharmacogenetics 2008 for Med Students
6/58
Challenges to drug designChallenges to drug design
8/8/2019 Pharmacogenetics 2008 for Med Students
7/58
Drug responses are genetic!Drug responses are genetic!
Drug metabolism/response can beDrug metabolism/response can be
monogenicmonogenic
alteration of the key metabolizing enzyme canalteration of the key metabolizing enzyme can
alter drugs effectalter drugs effect
Drug responses are polymorphicDrug responses are polymorphic
Drugs trigger downstream events that can varyDrugs trigger downstream events that can vary
among patientsamong patients
8/8/2019 Pharmacogenetics 2008 for Med Students
8/58
Drug response curveDrug response curve
8/8/2019 Pharmacogenetics 2008 for Med Students
9/58
Variation in drug response can beVariation in drug response can be
hereditaryhereditary
Variations in absorption ratesVariations in absorption rates
Variations in drug metabolismVariations in drug metabolism
Variations in drugVariations in drug
inactivation/eliminationinactivation/elimination Variation in target receptorsVariation in target receptors
8/8/2019 Pharmacogenetics 2008 for Med Students
10/58
How genes alter drug responses:How genes alter drug responses:
Hereditary metabolic disorders thatHereditary metabolic disorders that
alter drug metabolismalter drug metabolism
Genetic variants of drugGenetic variants of drug
metabolizing enzymesmetabolizing enzymes
Genetic variants of drug receptorsGenetic variants of drug receptors
8/8/2019 Pharmacogenetics 2008 for Med Students
11/58
Examples of genetic variationExamples of genetic variation
in drug metabolismin drug metabolism
Variants of plasma pseudocholinesteraseVariants of plasma pseudocholinesterase
experience prolonged apnea when treated withexperience prolonged apnea when treated with
the muscle relaxant succinylcholinthe muscle relaxant succinylcholin
Variants of AcetyltransferaseVariants of Acetyltransferase
Slow metabolizers experience toxic neuritis,Slow metabolizers experience toxic neuritis,
lupus and bladder cancer when treated withlupus and bladder cancer when treated withantianti--arrhythmic drug (procainamide)arrhythmic drug (procainamide)
Rapid metabolizers can experience colonRapid metabolizers can experience colon
cancercancer
8/8/2019 Pharmacogenetics 2008 for Med Students
12/58
Hereditary metabolic disordersHereditary metabolic disorders
that alter drug metabolismthat alter drug metabolism
GG--66--PD deficiencyPD deficiency -- can cause hemolysiscan cause hemolysis
when exposed to antiwhen exposed to anti--malaria drugsmalaria drugs
FactorV Leiden alleleFactorV Leiden allele -- increases risk ofincreases risk of
venous thrombosis (dont use oralvenous thrombosis (dont use oral
contraceptives in these women)contraceptives in these women)
LeschLesch--Nyhan SyndromeNyhan Syndrome -- chemo and goutchemo and gout
treatments are ineffective (the drugs are nottreatments are ineffective (the drugs are not
metabolized to their active form)metabolized to their active form)
8/8/2019 Pharmacogenetics 2008 for Med Students
13/58
Genetic Variation & PolymorphismGenetic Variation & Polymorphism
influence metabolisminfluence metabolism
Alcohol dehydrogenaseAlcohol dehydrogenase -- three loci; variantthree loci; variant
of ADH2 much more common in Japaneseof ADH2 much more common in Japanese
(90%) than Europeans (15%)(90%) than Europeans (15%)
Lactose activityLactose activity two major alleles; lowtwo major alleles; low
activity allele more common in Africansactivity allele more common in Africans
and Asiansand Asians
8/8/2019 Pharmacogenetics 2008 for Med Students
14/58
Drug MetabolismDrug Metabolism
Gene XGene X
Enzyme XEnzyme X
Drug ADrug A Substance ASubstance A
8/8/2019 Pharmacogenetics 2008 for Med Students
15/58
Variants of drug metabolism
Variants of drug metabolism
Variant ofGene XVariant ofGene X
Enzyme X Enzyme X
Drug ADrug A Substance ASubstance A
8/8/2019 Pharmacogenetics 2008 for Med Students
16/58
Genetic variants that decrease levels ofGenetic variants that decrease levels of
drug metabolizing enzymesdrug metabolizing enzymes
Variant ofGene XVariant ofGene X
Enzyme XEnzyme X
Drug ADrug A Substance ASubstance A
8/8/2019 Pharmacogenetics 2008 for Med Students
17/58
Genetic variants that result in overGenetic variants that result in over
production of metabolizing enzymeproduction of metabolizing enzyme
Variant of Gene XVariant of Gene X
Enzyme XEnzyme X
Drug A
Drug A Substance ASubstance A
8/8/2019 Pharmacogenetics 2008 for Med Students
18/58
Genetic Variants in DrugGenetic Variants in Drug
ReceptorsReceptors
Gene XGene X
Receptor XReceptor X
Drug ADrug A Cascade ofCascade of
cellular eventscellular events
8/8/2019 Pharmacogenetics 2008 for Med Students
19/58
Genetic variants in drug receptorsGenetic variants in drug receptors
Variant ofGene XVariant ofGene X
Aberrant Receptor XAberrant Receptor X
Drug ADrug A Cascade ofCascade of
cellular eventscellular events
8/8/2019 Pharmacogenetics 2008 for Med Students
20/58
Over (or under) expression ofOver (or under) expression of
receptors can alter drug responsereceptors can alter drug response
8/8/2019 Pharmacogenetics 2008 for Med Students
21/58
Mutant receptors may not bind the drug;Mutant receptors may not bind the drug;
therefore, altering drug responsetherefore, altering drug response
(may look like drug resistance)(may look like drug resistance)
8/8/2019 Pharmacogenetics 2008 for Med Students
22/58
Genetic variation in drugGenetic variation in drug
receptorsreceptors
SteroidSteroid--induced glaucoma (dexamethasone)induced glaucoma (dexamethasone)
Malignant hyperthermia (general anesthesia)Malignant hyperthermia (general anesthesia) Anticoagulant resistance (Coumarin,Anticoagulant resistance (Coumarin,
warfarin) requires 7warfarin) requires 7--20X more drug to get a20X more drug to get a
responseresponse
Retinoic Acid suppression of leukemiaRetinoic Acid suppression of leukemia
Vasopressin resistanceVasopressin resistance
8/8/2019 Pharmacogenetics 2008 for Med Students
23/58
Warfarin = coumadinWarfarin = coumadin
Warfarin inhibitsWarfarin inhibits
vitamin K reductase,vitamin K reductase,
which is the enzymewhich is the enzymeresponsible for recyclingresponsible for recycling
oxidated vitamin Koxidated vitamin K
back into the system.back into the system.
For this reason, drugs inFor this reason, drugs inthis class are alsothis class are also
referred to as vitamin Kreferred to as vitamin K
antagonists.antagonists.
8/8/2019 Pharmacogenetics 2008 for Med Students
24/58
WarfarinWarfarin
Discovered 60 years ago and oneDiscovered 60 years ago and one
of the most widely prescribed drugs in the worldof the most widely prescribed drugs in the world Intended to prevent and treat thromboembolismsIntended to prevent and treat thromboembolisms
Afib, recurrent stroke, DVT, pulmonary embolism, heartAfib, recurrent stroke, DVT, pulmonary embolism, heartvalve prosthesisvalve prosthesis
MultiMulti--source anticoagulantsource anticoagulant 1, 2, 2.5, 3, 4, 5, 6, 7.5 and 10 mg tablet strengths1, 2, 2.5, 3, 4, 5, 6, 7.5 and 10 mg tablet strengths
Significant increase in Rxs over past 10 yearsSignificant increase in Rxs over past 10 yearsespecially in the elderlyespecially in the elderly
8/8/2019 Pharmacogenetics 2008 for Med Students
25/58
Trends inWarfarin Use: 1.5Trends inWarfarin Use: 1.5--foldfold
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 YTD
9/2005Year
Dis
pensedR
(millions)
Source: IMS Health National Prescription AuditPlusTM Data Extracted 11/2005
8/8/2019 Pharmacogenetics 2008 for Med Students
26/58
Safety ofW
arfarinSafety ofW
arfarinMajor risk is bleeding: frequent
and severe
1.2 7 major bleeding episodesper 100 patients
Responsible for 1 in 10 hospital
admissions
Relative risk of fatal extracranial
bleeds 0 - 4.8%
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
8/8/2019 Pharmacogenetics 2008 for Med Students
27/58
PurplePurple--toe syndrome & skin necrosistoe syndrome & skin necrosis::rare adverse reactions to warfarinrare adverse reactions to warfarin
8/8/2019 Pharmacogenetics 2008 for Med Students
28/58
DosingDosing ofW
arfarin isC
omplex
ofW
arfarin isC
omplex
Narrow therapeutic indexNarrow therapeutic index
Small separation between doseSmall separation between dose--response curvesresponse curves
for preventing emboli and excess coagulationfor preventing emboli and excess coagulation Nonlinear doseNonlinear dose--response (INR)response (INR)
Small changes in dose may cause large changesSmall changes in dose may cause large changesin INR with a time lagin INR with a time lag
Wide range (50x) of doses (2Wide range (50x) of doses (2--112 mg/week)112 mg/week)to achieve target INR of 2to achieve target INR of 2--33
Patient intrinsic and extrinsic factorsPatient intrinsic and extrinsic factors
8/8/2019 Pharmacogenetics 2008 for Med Students
29/58
DNA testing forDNA testing for
Warfarin sensitivity
Warfarin sensitivityThe FDA Clinical PharmacologyThe FDA Clinical Pharmacology
Subcommittee of the Advisory CommitteeSubcommittee of the Advisory Committee
for Pharmaceutical Sciences hasfor Pharmaceutical Sciences hasrecommended testing for variations in therecommended testing for variations in the
CYP2C9 and VKORC1 in patientsCYP2C9 and VKORC1 in patients
requiring warfarin therapy. The drug labelrequiring warfarin therapy. The drug label
will reflect this recommendation soon.will reflect this recommendation soon.
Article on this testArticle on this test
8/8/2019 Pharmacogenetics 2008 for Med Students
30/58
Warfarin MetabolismWarfarin Metabolism
Two polymorphic genes, CYP2C9 andTwo polymorphic genes, CYP2C9 andVKORC1, affect warfarin metabolism andVKORC1, affect warfarin metabolism andresponse. Allelic frequencies of these two genesresponse. Allelic frequencies of these two genesare usually associated with ethnicity. Here areare usually associated with ethnicity. Here arethe concerns with prescribing warfarin tothe concerns with prescribing warfarin topatients with CYP2C9 or VKORC1patients with CYP2C9 or VKORC1polymorphisms:polymorphisms:
Overdose can result in bleeding which can beO
verdose can result in bleeding which can befatal.fatal.
Under dose can result in thrombosis which canUnder dose can result in thrombosis which canbe fatalbe fatal
8/8/2019 Pharmacogenetics 2008 for Med Students
31/58
VKORC1 VariantsVKORC1 Variants
VKORC1 polymorphisms may explain up toVKORC1 polymorphisms may explain up to
25% of patient variability in response to25% of patient variability in response to
warfarin. Patients with VKORC1warfarin. Patients with VKORC1
polymorphisms are at risk for exaggeratedpolymorphisms are at risk for exaggerated
anticoagulant response.anticoagulant response.
8/8/2019 Pharmacogenetics 2008 for Med Students
32/58
CYP2C9VariantsCYP2C9Variants
CYP2C9 variants take more time to achieveCYP2C9 variants take more time to achieve
stable dosing, and are associated withstable dosing, and are associated with
increased risk of bleeding events. Lowincreased risk of bleeding events. Low
CYP2C9 activity results in higher plasmaCYP2C9 activity results in higher plasma
levels of warfarin so the patient is at risk forlevels of warfarin so the patient is at risk for
bleedingbleeding
8/8/2019 Pharmacogenetics 2008 for Med Students
33/58
Warfarin Sensitivity
Warfarin Sensitivity
TheWarfarin Sensitivity DNA TestTheWarfarin Sensitivity DNA Testdetermines the presence of specificdetermines the presence of specific
variations in the CYP2C9 and VKORC1variations in the CYP2C9 and VKORC1genes that confer sensitivity to warfaringenes that confer sensitivity to warfarin
and thus significantly reduce theand thus significantly reduce therequired maintenance dose. CYP2C9 isrequired maintenance dose. CYP2C9 is
involved in warfarin metabolism andinvolved in warfarin metabolism andVKORC1 influences warfarin'sVKORC1 influences warfarin's
anticoagulation effect through vitamin K.anticoagulation effect through vitamin K.
8/8/2019 Pharmacogenetics 2008 for Med Students
34/58
Mechanistic Basis of DosingMechanistic Basis of Dosing
ProblemProblem
Large interindividual variability related to SLarge interindividual variability related to S--warfarinwarfarin
metabolism by CYP2C9 (genetics)metabolism by CYP2C9 (genetics)
*1 (wild type), *2 and *3 (variant alleles)*1 (wild type), *2 and *3 (variant alleles)
GenotypeGenotype
(N = 188)(N = 188)
PrevalencePrevalence % Enzyme% Enzyme
ActivityActivity
S/RS/R
WarfarinWarfarin
(mg/L)(mg/L)
WeeklyWeekly
DosesDoses
(mg)(mg)
Clearance/LClearance/L
BWBW
(ml/min/kg(ml/min/kg))
2C9 *1/*12C9 *1/*1 63%63% 100%100% 0.450.45
(0.11)(0.11)
34.134.1
(19.5)(19.5)
0.065 (0.025)0.065 (0.025)
2C9 *1/*X2C9 *1/*X 31%31% 5050--70%70% 0.690.69
(0.28)(0.28)
19.019.0
(10.8)(10.8)
0.041 (0.021)0.041 (0.021)
2C9 *X/*X2C9 *X/*X 6%6% 10%10% 1.431.43
(0.63)(0.63)
11.511.5
(7.2)(7.2)
0.020 (0.011)0.020 (0.011)
Herman et al, The Pharmacogenomics J 4:1-10. 2005
8/8/2019 Pharmacogenetics 2008 for Med Students
35/58
Dosing Adjustments Based onDosing Adjustments Based on
GenotypeGenotype--Specific SSpecific S--WarfarinWarfarin
ClearanceClearance
0%
20%
40%
60%
80%
100%
PD
RRecommendedDose,
%
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
8/8/2019 Pharmacogenetics 2008 for Med Students
36/58
Iressa: cancer miracle drugIressa: cancer miracle drug
Epidermal growth factorEpidermal growth factor
receptorreceptor--tyrosine kinase inhibitortyrosine kinase inhibitor
Used as a single treatment agent forUsed as a single treatment agent for
nonnon--small cell lung cancersmall cell lung cancer
Seems to work best on patientsSeems to work best on patients
with lung cancer who never smokedwith lung cancer who never smoked
It works by blocking tyrosine kinases found on the surface of normal &It works by blocking tyrosine kinases found on the surface of normal &
cancer cellscancer cells
Works on metastatic tumors as well.Works on metastatic tumors as well.
8/8/2019 Pharmacogenetics 2008 for Med Students
37/58
Genetic variants in drugGenetic variants in drug
metabolismmetabolism
Fluorouracil (5Fluorouracil (5--FU) ToxicityFU) Toxicity
55--FU is a very common chemo agent for solid tumorsFU is a very common chemo agent for solid tumors
dihydropyrimidine dehydrogenase deficiency (DPD)dihydropyrimidine dehydrogenase deficiency (DPD)
increases the half life of 5increases the half life of 5--FU from 13 min to 160FU from 13 min to 160
min (prolonged exposure to the drug)min (prolonged exposure to the drug)
Incidence of this variant is 1Incidence of this variant is 1--3% of cancer patients3% of cancer patients The prolonged exposure to all tissues results inThe prolonged exposure to all tissues results in
toxicity, primarily BM and GI (neuro occassionally)toxicity, primarily BM and GI (neuro occassionally)
8/8/2019 Pharmacogenetics 2008 for Med Students
38/58
Genetic variants in drugGenetic variants in drug
metabolismmetabolism
Thiopurine methyltransferase null variantsThiopurine methyltransferase null variants
incidence of about 1 in 300incidence of about 1 in 300
Pts. Cannot metabolize chemo drugs used toPts. Cannot metabolize chemo drugs used totreat leukemia(6treat leukemia(6--mercaptopurine, 6mercaptopurine, 6--thioguaninethioguanine
& azathioprine) into their inactive methylated& azathioprine) into their inactive methylated
formsforms
Pts. Can be treated with 10Pts. Can be treated with 10--15 times less chemo15 times less chemo
than commonly prescribedthan commonly prescribed
Genotyping or functional enzyme assay is nowGenotyping or functional enzyme assay is now
the STANDARD PRACTICE in cancer centersthe STANDARD PRACTICE in cancer centers
8/8/2019 Pharmacogenetics 2008 for Med Students
39/58
8/8/2019 Pharmacogenetics 2008 for Med Students
40/58
Genetic variants in drugGenetic variants in drug
metabolismmetabolism
Slow acetylator phenotype results inSlow acetylator phenotype results in
peripheral neuropathy in pts treated with antiperipheral neuropathy in pts treated with anti--
TB drug (isoniazid)TB drug (isoniazid)
Causes slow clearance of the drug andCauses slow clearance of the drug and
associated toxicityassociated toxicity
This phenotype is found in 40This phenotype is found in 40 --60% of60% of
Caucasians, 80% of Middle Eastern pop butCaucasians, 80% of Middle Eastern pop but
only 20% of Japanese pop.only 20% of Japanese pop.
8/8/2019 Pharmacogenetics 2008 for Med Students
41/58
8/8/2019 Pharmacogenetics 2008 for Med Students
42/58
8/8/2019 Pharmacogenetics 2008 for Med Students
43/58
Variants ofCytochrome P450Variants ofCytochrome P450
Cytochrome P450 enzymes are responsibleCytochrome P450 enzymes are responsible
for the MAJOR portion of drug metabolismfor the MAJOR portion of drug metabolism
CYP2D6 null alleles result in poorCYP2D6 null alleles result in poor
metabolizers and adverse reactions to cardiometabolizers and adverse reactions to cardio
and psyc medicationsand psyc medications
CYP2C9 mutations result in 5X decline inCYP2C9 mutations result in 5X decline inmetabolism of drugs (ibuprofen,metabolism of drugs (ibuprofen,
naproxen,etc)naproxen,etc)
8/8/2019 Pharmacogenetics 2008 for Med Students
44/58
Genetic variations in the rate of drugGenetic variations in the rate of drug
metabolism can be specific for certainmetabolism can be specific for certain
ethnic groupsethnic groups
8/8/2019 Pharmacogenetics 2008 for Med Students
45/58
8/8/2019 Pharmacogenetics 2008 for Med Students
46/58
8/8/2019 Pharmacogenetics 2008 for Med Students
47/58
Gleevec:Gleevec:
pharmacogenetics in action!pharmacogenetics in action! Used to treat CMLUsed to treat CML
4,500 middle4,500 middle--aged Americans diagnosed withaged Americans diagnosed with
CML each yearCML each year
Designed to block the activity of the BCRDesigned to block the activity of the BCR--
ABL proteinABL protein
BCRBCR--ABL is a fusion protein produced by theABL is a fusion protein produced by the
9;22 translocation associated with this9;22 translocation associated with this
leukemialeukemia
8/8/2019 Pharmacogenetics 2008 for Med Students
48/58
8/8/2019 Pharmacogenetics 2008 for Med Students
49/58
8/8/2019 Pharmacogenetics 2008 for Med Students
50/58
8/8/2019 Pharmacogenetics 2008 for Med Students
51/58
SNPs = Single NucleotideSNPs = Single Nucleotide
PolymorphismsPolymorphisms
Occur throughout the genomeOccur throughout the genome
Occur about every 1,000 basesOccur about every 1,000 bases
May be linked toMay be linked to
polymorphisms in drug responspolymorphisms in drug respons
Under intense study byUnder intense study by
pharmaceutical companies.pharmaceutical companies.
8/8/2019 Pharmacogenetics 2008 for Med Students
52/58
SNPs are throughout the genomeSNPs are throughout the genome
8/8/2019 Pharmacogenetics 2008 for Med Students
53/58
SNPsSNPs
Characterization of SNPsCharacterization of SNPs
may help in identifyingmay help in identifying
subsets of individuals atsubsets of individuals atrisk for specificrisk for specific
diseasesdiseases
SNPs may predict drugSNPs may predict drugresponses/adverseresponses/adverse
reactionsreactions
8/8/2019 Pharmacogenetics 2008 for Med Students
54/58
8/8/2019 Pharmacogenetics 2008 for Med Students
55/58
Gene Expression Analysis usingGene Expression Analysis using
MicroarraysMicroarrays
T i t P fili A h fT i t P fili A h f
8/8/2019 Pharmacogenetics 2008 for Med Students
56/58
Copyright restrictions may apply.
Bumol, T. F. et al. JAMA 2001;285:551-555.
Transcript Profiling Approach forTranscript Profiling Approach for
Understanding Novel DrugUnderstanding Novel Drug
MechanismsMechanisms
8/8/2019 Pharmacogenetics 2008 for Med Students
57/58
8/8/2019 Pharmacogenetics 2008 for Med Students
58/58
PharmacogenomicsPharmacogenomics
therapy with theright drug at the
right dose in the
right patient