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Pharmacogenetics: 7 questions about highly effective implementation
Prof. dr. Henk-Jan Guchelaar
Clinical Pharmacy & Toxicology
Leiden University Medical Center
Leiden Academic Center for Drug Research
Spanish Society of Hospital Pharmacy meeting
Madrid, 31 January 2013
2
Disclosures (January 2013)
• Institutional
• Patent EP 06119819.8 and US 60/840,973 (MTX efficacy)
• Tamoxifen prospective study (CYPTAM) (Roche, Amplichip®)
• Personal
• None declared
Leiden University Medical Center
3
4
Translational Drug Research
Leiden University Medical Center Leiden Academic Center
for Drug Research
Two patients at your outpatient clinic
• Two patients A and B
• The same symptoms
• The same doctor
• The same diagnostic procedures
• The same diagnosis X
• The same treatment
• Drug Rx at a dose x mg/day
• After 3 weeks
• Patient A: symptoms resolved
• Patient B: still symptoms, side effects
• How is this possible?
5
6
Pharmacogenetics: drug response is a heritable trait
7 Questions
•Q1: Do we need biomarkers to predict
drug response?
7
8
‘Most drugs don’t work’
Effective (%)…..
• Alzheimer 30
• Depression (SSRI) 62
• Asthma 60
• Diabetes mellitus 57
• Incontinence 40
• Migraine (acute) 52
• Migraine (profyl.) 50
• Cradiac dysrhythmia 60
• Tumors 25
• Schizophrenia 60
• Reumatoid arthritis 50
• Reumat. art. (Cox-2) 80
• Hepatitis C 47 Spear, Trends Mol Med 2001;7(5):201
Clinical Drug Toxicity
• Harvard Medical Practice Study – Lucian Leape
• Nature of adverse events in hospitalized patients
• 30,195 randomly selected patients records
• 1,113 (= 3.7%) disabling injury caused by medical treatment
• 19% adverse drug events (ADEs)
• Hospital Admissions Related to Medication
• Incidence of hospital admissions related to drug related problems
• 21 hospitals in The Netherlands
• 5.6% of acute admissions were drug related: 50% preventable
9
Prescribing drugs – Trial and Error
10
Dx Guideline
Rx Clinical studies
•Dx
•Inclusion criteria
•Age
•Organ function
•Severity of disease
First choice Drug
•‘Normal’ dose
•Individualize
•Co-morbidity
•Co-medication
•Age, Organ function
Monitor effect
•Efficacy & Toxicity
•Tumorsize, Biomarkers
•Pain(score), Bloodpressure
•Cholesterol levels
•Liverfunction, Myalgia
Drug dose
•Increase/decrease
Switch drug
•Second choice Drug
11 11
Individualization of drug therapy
100% dose
DRUG A
50% dose
DRUG A
DRUG B
DNA Test
• High Blood Pressure
• Antihypertensive drug: 2-4 wks
BP cardiovascular risk
• Consequences of delay of efficacious
treatment
• 3 months
• 10 yr (= 120 mo) treatment may
result in an absolute risk reduction
of 2,5% of 10 years risk death
• absolute risk: 7,50% 7.56%
12
Monitoring drug effects – ‘Trial and Error’ prescribing
• Metastatic colorectal cancer
• 3-6 courses chemotherapy: 9-18
weeks CT-scan response
• Consequences of delay of
efficacious treatment
• 2-4 months
• mCRC: OS= 24 months
13
Monitoring drug effects – ‘Trial and Error’ prescribing
Biomarkers needed for predicting drug response
• Drug effect presents after
months-years
• Important clinical
consequences of treatment
delay
• Diseases with a poor
prognosis
• Severe side effects
14
7 Questions
•Q2: Which are the sources of heritable
variability in drug response?
15
Sources of variability in drug response
16
Compliance
Absorption
Metabolism
Elimination
Target/Receptor
Signal transduction
Concentration-effect relationship
Toxicity
Inefficacy
CONC
TIME
Poor metabolizer
Ultrarapid metabolizer
Genetic variants encoding drug receptor
18
receptor-agonist
Sunitinib toxicity – Pharmacogenetic biomarkers
19
20
• 219 patients treated with sunitinib from five
Dutch medical centers
• mRCC (159), GIST (50), other (10)
• Toxicity was evaluated in first treatment cycle
(6 weeks) by NCI–CTC-AE version 3.0
• Aim was to identify genetic markers in the PK
and PD pathway of sunitinib that predispose for
toxicity
• 31 single nucleotide polymorphisms in 12
candidate genes – PK and PD sunitinib
Van Erp, J Clin Oncol 2009:27(26):4406-12
Sunitinib toxicity – Pharmacogenetic biomarkers
21
RET
1580T/C
-1171C/G
-735G/A
-573G/T
738T/C 2251G/A -604T/C
-92G/A
54T/C
1191C/T
1718T/A
1501A/G
Pharmacodynamics
Van Erp, J Clin Oncol 2009:27(26):4406-12
1501A/G
22
Sunitinib Metabolites
SU12662 (active) and inactive metabolites
ABCB1 (Pgp) (3435C/T, 1236C/T, 2677G/T)
ABCG2 (BCRP) (421C/A, 34G/A, -15622C/T, 1143C/T)
CYP3A4 (
CYP3A5 (6986A/G)
CYP1A1 (2455A/G)
CYP1A2 (-163A/C)
NR1I2 (-25385C/T, -24113G/A,
7635A/G, 8055C/T, 10620C/T, 10799G/A )
NR1I3 (5719C/T, 7738A/C, 7837T/G)
Pharmacokinetics
Van Erp, J Clin Oncol 2009:27(26):4406-12
23
• Leukopenia
• CYP1A1 2455A/G OR= 6.24
• FLT3 738T/C OR= 2.8
• NR1I3 haplotype OR= 1.74
• Any toxicity > grade 2
• VEGFR2 1191C/T OR= 2.39
• ABCG2 haplotype OR= 2.63
• Mucositis
• CYP1A1 2455A/G OR= 4.03
• Handfoot syndrome
• ABCB1 haplotype OR= 2.56
Van Erp, J Clin Oncol 2009:27(26):4406-12
Sunitinib toxicity – Pharmacogenetic biomarkers
Sunitinib efficacy - Pharmacogenetic biomarkers
• Identify predictive biomarkers for
sunitinib efficacy in mRCC
• 136 mRCC ‘clear cell’
• PFS/OS
• 31 ‘single nucleotide
polymorphisms’ in 12 candidate
genes – PK en PD sunitinib
• Clinical characteristics
24 Van der Veldt, Clin Cancer Res 2011;17(3):620-9
25
PFS OS
Favorable profile: (n=95) at least an A-allele in CYP3A5, a TCG copy in the
ABCB1 haplotype or a missing CAT copy in the NR1I3 haplotype
Median PFS: 13.1 mo vs 7.5 mo (p= 0.001)
Median OS: 19.9 mo vs 12.3 mo (p= 0.009)
Sunitinib efficacy - Pharmacogenetic biomarkers
Van der Veldt, Clin Cancer Res 2011;17(3):620-9
7 Questions
•Q3: How much variance is explained by
pharmacogenetics?
26
27
How much variance is explained by pharmacogenetics?
Tamoxifen – CYP2D6
28
O
N
H
CH3
CH3
OH
O
N
H
CH3
CH3
O
N
CH3
CH3
CH3
O
N
CH3
CH3
CH3
OH
TAMOXIFEN 4-OH-TAM
NDM-TAM ENDOXIFEN
CYP2D6
CYP2B6
CYP2C9
CYP2C19
CYP3A
CYP2D6
CYP3A4/5
CYP1A2
CYP2C9
CYP2C19
CYP2D6
Tamoxifen metabolism
CYP3A4/5
SULT1A1
UGT
SULT1A1
UGT
Dezentje, Clin Cancer Res 2009;15(1):15-21
30
Genotype to phenotype translation
Roche, AmpliChip CYP450 Test, manual
E
Goetz, 2005
Presentation SABCS ‘09
CYP2D6 genotype association studies
Positive studies
N HR p
Goetz ’05 190 1.86 .08
Schroth ’07 197 1.89 .02
Newman ’08 68 3.6 .09
Ramon ’09 91 >1 .02
Bijl ’09 85 2.1 .03
Kiyotani ’08/’10 282 9.5 <.001
Xu ’08 152 4.7 .04
Lim ’07 21 .02
Bonanni ’06/’10 182 .04
Schroth ’09 1325 1.29 .02
Negative studies
N HR p
Wegman ’05 76 <1 NS
Wegman ’07 677 <1 .055
Nowell ’05 162 .67 .19
Okishiro ’09 173 .6 .39
Toyamo ’09 154 NS
Dieudonnée ’09
Dezentje’10 747 1 NS
Goetz 2,880 NS
Dezentje, ASCO 2010
33
CYP2D6 genotype – endoxifen concentration
Jin, J Natl Cancer Inst ; 2005:30
wt/wt = no *3, *4, *5 or *6
wt/vt = one *3, *4, *5 of *6 allel
vt/vt = *4/*4
• 13C dextrometorphan breath test
34
CYP2D6 phenotype – endoxifen concentration
Opdam, Cancer Chemother Pharmacol. 2012 Dec 11
Explained variance
35
Drug (Genetic) variant R2 Variable
Warfarin VKORC1 25% dose requirement
+BSA 34%
+CYP2C9*3 40%
+Age 45%
+CYP2C9*2 50%
Acenocounarol CYP2C9 4.9% dose requirement
VKORC1 21.4% dose requirement
Irinotecan UGT1A1 *28 24% neutropenia
Methotrexaat sex + Rf status + smoking 35% DAS response
+DAS at baseline +
AMPD1 + ATIC + ITPA
+ MTHFD1
7 Questions
•Q4: How much evidence is needed for
implementation?
36
Implementation PGx: How much evidence is needed?
• Randomized Clinical Trial
• Endpoints: safety and efficacy
• Cost-effectiveness
• Observational evidence
• Well powered, well designed
• Including replication studies
• Compare with dose adjustments
• Decreased renal function
• Drug interactions
37 Van Wielen, Pharmacogen 2011;12(9):1231
38 38
Abacavir – HLA-B *5701 screening
• 1,956 patients
• 1:1 randomized: screening versus no screening
• Prevalence HLA-B *5701= 5,6% (109 patients)
• NPV= 100%; PVV= 48%
Mallal, N Engl J Med 2008;358(6):568
7 Questions
•Q5: Is the pharmacogenetic test result
actionable?
39
Actionable predictive biomarkers
• Endpoint current PGx
studies:
• OR= 1.90
• (Un)favorable genetic profile
• Increased risk
• Association with ..
• Relationship ..
• …
• Dosing algorithm
• Decision tree
• Scoring system
• Clinical guidelines
40
41
Predictive model: scoring system MTX efficacy in RA
Baseline Variable Score
premenopausal 1 Gender Female
postmenopausal 1
Male 0
Disease activity DAS at baseline 3.8 0
DAS at baseline >3.8, but 5.1 3
DAS at baseline >5.1 3.5
Immunological factors Rheumatoid factor negative and non - smoker 0
Rheumatoid factor negative and smoker 1
Rheumatoid factor positive and non - smoker 1
Rheumatoid factor positive a nd smoker 2
Genetic factors MTHFD1 1958 AA genotype 1
AMPD1 34 CC genotype 1
ITPA 94 A - allele carrier 2
ATIC 347 G - allele carrier 1
Other ge notypes 0
Baseline Variable Score
premenopausal 1 Gender Female
postmenopausal 1
Male 0
Disease activity DAS at baseline 3.8 0
DAS at baseline >3.8, but 5.1 3
DAS at baseline >5.1 3.5
Immunological factors Rheumatoid factor negative and non - smoker 0
Rheumatoid factor negative and smoker 1
Rheumatoid factor positive and non - smoker 1
Rheumatoid factor positive a nd smoker 2
Genetic factors MTHFD1 1958 AA genotype 1
AMPD1 34 CC genotype 1
ITPA 94 A - allele carrier 2
ATIC 347 G - allele carrier 1
Other ge notypes 0
≤
≤
Wessels, Arthritis & Rheum 2007;56(6):1765
Sum of score = ……………………………………………………...
42
Good clinical response
Good clinical
response (proportion
at t= 6 months)
Wessels, Arthritis & Rheum 2007;56(6):1765
7 Questions
•Q6: Is pharmacogenetic testing feasible?
43
Costs
$1
$10
$100
$1.000
$10.000
$100.000
$1.000.000
$10.000.000
$100.000.000
$1.000.000.000
sep-
01
sep-
02
sep-
03
sep-
04
sep-
05
sep-
06
sep-
07
sep-
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sep-
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sep-
10
Wetterstrand KA. www.genome.gov/sequencingcosts
Genotyping technology
45
Taqman
Pyrosequenching
High Resolution Melting
46
DNA-chip technology
Amplichip
33 CYP2D6 variants
3 CYP2C19 variants DMET-Plus array
Drug Metabolizing Enzymes and Transporters
1,936 variants in 225 genes
47
Affymetrix fluidic station 450Dx en Scanner 3000Dx
Pharmacogenetic service: genotyping and consult
48
http://www.lumc.nl/con/3092/
Do patients want PGx screening?
• Feasibility of pharmacy-initiated
pharmacogenetic screening for CYP2D6
and CYP2C19 in primary care setting
• Polypharmacy patients; >60 yrs
• Screening; no ADE
• Provided informed consent: 58.1%
• DNA extraction (Oragene®): 83.3%
• Call rate:
• 93.3% CYP2D6
• 100% CYP2C19
• Guideline application dispensing records:
100%
49 Swen, Eur J Clin Pharmacol 2011, 8 Oct
7 Questions
•Q7: Where do I find up to date information
for interpretation of pharmacogenetic test
results?
50
Adoptation of PGx by US Physicians: National survey
• To benchmark physicians’ level
of knowledge and extent of use
of PGx testing
• 397,832 questionnaires
• 10,303 respondents
• 97.6% agreed that genetic
variations may influence drug
response
• 10.3% felt adequately informed
about PGx
• 29% had received any PGx
education
• 12.9% had ordered a PGx test
(6 mo)
Stanek, Clin Pharmacol Ther 2012;91(3):450
Difficulties in interpretation
• One gene – one drug
• TPMT – mercaptopurine
• UGT1A1 – irinotecan
• HLA *5701 - abacavir
• One gene – many drugs
• CYP2D6, CYP2C19
• polypharmacy
• More genes – one drug
• Tricyclic antidepressants
• More genes – many drugs
• Pharmacological knowledge
clinical pharmacist
• Drug metabolism, interactions
52
Pharmacists’ expectations towards pharmacogenetics
• To describe the expectations, opinions
and concerns of pharmacists
• Survey 284 pharmacists in Quebec
(Canada)
• 59% community pharmacy
• 28% hospital pharmacy
• 95.6% would be willing to
recommend testing
• 7.7% currently felt comfortable
advising patients
• 96.6% would like to undertake
education on pharmacogenetics
53 De Denus, Pharmacogenomics 2013;14(2):165
Pharmacists?
54
56
Level of Evidence and Clinical Relevance gene-drug interaction
Swen, Clin Pharmacol Ther 2008;83(5):781-8
Swen et al, Clin Pharmacol Ther. 2011 ;89(5):662
Discharge recipe
59
Clinical rule DPYD genotyping
New Prescription
Capecitabine, 5-Fluorouracil,
Tegafur?
Pop up: Please send bloodsample to
pharmacy for DPYD genotyping
Result genotyping DPYD*2A
(rs3918290)
PM Prescribe an alternative drug
IM Reduce the starting dose to
50%; then dose intensification
upon toxicity
EM Standard dose
Yes
Yes
Former prescription for
Capecitabine, Fluorouracil, Tegafur?
No
Yes
Is DPYD*2A
genotype known?
Is DPYD*2A
genotype known?
No
Yes
Rule not applicable No
No
Yes
www.pharmgkb.org
61
Dosing
guidelines
Dutch Pharmacogenetics Working Group
www.pharmgkb.org
How did we start pharmacogenetics in Leiden?
• Research driven
• Oncology and rheumatology
• Grant applications
• Publications
• Laboratory for Experimental and Clinical Pharmacogenetics
• Molecular biologist
• Assistant professor in pharmacogenetics
• Implementation clinical practice
• Development guidelines for interpretation tests
• Promoting testing in the clinic
• Electronic prescribing (ordering tests, medication surveillance)
• Education
• Training pharmacists, students
63
Personal view for PGx (germline) testing recommendations
• TPMT – thiopurines
• CYP2C19 – clopidogrel
• CYP2C9-VKORC1 – coumarines
• DPYD – 5FU/capecitabine
• HLA-B – abacavir/carbamazepine
• G6PD – rasburicase
• UGT1A1 – irinotecan
• IL28B – pegintron
• SLCO1B1 – statine + spierpijn
• CYP2D6 – tamoxifen
• CYP3A5 - tacrolimus
• If I was a patient
64
Conclusions
• Drug response is a heritable trait
• Biomarkers are needed for predicting drug response
• Polygenetic markers in both the PK and PD predispose for toxicity and
efficacy
• To increase the explained variance genetic markers should be combined
with other determinants of drug response
• Pharmacogenetic studies should report actionable results
• Observational evidence from well designed and replicated studies may be
acceptable to adjust the dose
• Pharmacogenetics is feasible in the clinic and well accepted by patients and
physicians
• Pharmacogenetic guidelines for interpretation of test results are available
• There is an opportunity for clinical pharmacists to fulfill a new clinical role as
an expert in PGx
65
66
Thanks to
Dr Tahar van der Straaten
Laboratory for Experimental
and Clinical Pharmacogenetics
Prof dr Tom Huizinga Prof dr Hans Gelderblom
Dr Jesse Swen
Backup slides
67
7 Questions
•Q6b: Is pharmacogenetic testing feasible
in the pharmacy department?
68
Clinical Pharmacy & Toxicology LUMC
69
New GMP-facility (2012)
70
71
Cinical Pharmacy & Toxicology LUMC
Clinical Pharmacy
72
Bachelor Pharmacy
4 years
Master Pharmacy
2 years
Pharmacist (PharmD)
Hospital Pharmacy
4 years (zaio)
Clinical Pharmacist
Hospital Pharmacy
6 years (zapiko)
Clinical Pharmacist
(PharmD PhD)
Clin. Pharmacology – 1 year
Clin. Pharmacist/ Clin. Pharmacol.
Clinical Pharmacy Department
• Drug dispensing
• In patients
• Out patients
• Drug Manufacturing
• Laboratory
• QC/Drug levels-PK/Toxicology
• Pharmacogenetics
73
Integration of
74
expertise in clinical pharmac(olog)y in the framework of
Patient Care and Research
Identification – In depth analysis mechanisms – Translation to patient care
Typical PhD thesis – Jan Pander PharmD PhD
• Pharmacogenetics of advanced colorectal cancer treatment
• National CAIRO2 study
• PGx of EGFR and VEGF inhibition
• Clinical PGx association studies
• Pathway candidate gene approach
• GWAS study
• Translation to patient care
75
Typical PhD thesis – Jan Pander PharmD PhD
• Methodological
• Gene-gene interaction analysis in PGx
• Preclinical mechanistic studies
• Activation of tumor-promoting type 2 macrophages by cetuximab
76
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