Pharmacogenetics · •mRCC (159), GIST (50), other (10) •Toxicity was evaluated in first...
Transcript of Pharmacogenetics · •mRCC (159), GIST (50), other (10) •Toxicity was evaluated in first...
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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
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Disclosures (January 2013)
• Institutional
• Patent EP 06119819.8 and US 60/840,973 (MTX efficacy)
• Tamoxifen prospective study (CYPTAM) (Roche, Amplichip®)
• Personal
• None declared
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Leiden University Medical Center
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Translational Drug Research
Leiden University Medical Center Leiden Academic Center
for Drug Research
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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?
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Pharmacogenetics: drug response is a heritable trait
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7 Questions
•Q1: Do we need biomarkers to predict
drug response?
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‘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
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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
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Prescribing drugs – Trial and Error
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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
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11 11
Individualization of drug therapy
100% dose
DRUG A
50% dose
DRUG A
DRUG B
DNA Test
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• 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%
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Monitoring drug effects – ‘Trial and Error’ prescribing
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• 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
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Monitoring drug effects – ‘Trial and Error’ prescribing
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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
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7 Questions
•Q2: Which are the sources of heritable
variability in drug response?
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Sources of variability in drug response
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Compliance
Absorption
Metabolism
Elimination
Target/Receptor
Signal transduction
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Concentration-effect relationship
Toxicity
Inefficacy
CONC
TIME
Poor metabolizer
Ultrarapid metabolizer
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Genetic variants encoding drug receptor
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receptor-agonist
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Sunitinib toxicity – Pharmacogenetic biomarkers
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• 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
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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
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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
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• 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
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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
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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
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7 Questions
•Q3: How much variance is explained by
pharmacogenetics?
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How much variance is explained by pharmacogenetics?
Tamoxifen – CYP2D6
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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
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Genotype to phenotype translation
Roche, AmpliChip CYP450 Test, manual
E
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Goetz, 2005
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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
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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
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• 13C dextrometorphan breath test
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CYP2D6 phenotype – endoxifen concentration
Opdam, Cancer Chemother Pharmacol. 2012 Dec 11
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Explained variance
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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
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7 Questions
•Q4: How much evidence is needed for
implementation?
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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
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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
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7 Questions
•Q5: Is the pharmacogenetic test result
actionable?
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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
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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 = ……………………………………………………...
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Good clinical response
Good clinical
response (proportion
at t= 6 months)
Wessels, Arthritis & Rheum 2007;56(6):1765
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7 Questions
•Q6: Is pharmacogenetic testing feasible?
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Costs
$1
$10
$100
$1.000
$10.000
$100.000
$1.000.000
$10.000.000
$100.000.000
$1.000.000.000
sep-
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Wetterstrand KA. www.genome.gov/sequencingcosts
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Genotyping technology
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Taqman
Pyrosequenching
High Resolution Melting
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DNA-chip technology
Amplichip
33 CYP2D6 variants
3 CYP2C19 variants DMET-Plus array
Drug Metabolizing Enzymes and Transporters
1,936 variants in 225 genes
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Affymetrix fluidic station 450Dx en Scanner 3000Dx
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Pharmacogenetic service: genotyping and consult
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http://www.lumc.nl/con/3092/
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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
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7 Questions
•Q7: Where do I find up to date information
for interpretation of pharmacogenetic test
results?
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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
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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
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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
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Pharmacists?
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Level of Evidence and Clinical Relevance gene-drug interaction
Swen, Clin Pharmacol Ther 2008;83(5):781-8
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Swen et al, Clin Pharmacol Ther. 2011 ;89(5):662
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Discharge recipe
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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
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www.pharmgkb.org
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Dosing
guidelines
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Dutch Pharmacogenetics Working Group
www.pharmgkb.org
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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
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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
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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
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Thanks to
Dr Tahar van der Straaten
Laboratory for Experimental
and Clinical Pharmacogenetics
Prof dr Tom Huizinga Prof dr Hans Gelderblom
Dr Jesse Swen
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Backup slides
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7 Questions
•Q6b: Is pharmacogenetic testing feasible
in the pharmacy department?
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Clinical Pharmacy & Toxicology LUMC
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New GMP-facility (2012)
70
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Cinical Pharmacy & Toxicology LUMC
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Clinical Pharmacy
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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.
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Clinical Pharmacy Department
• Drug dispensing
• In patients
• Out patients
• Drug Manufacturing
• Laboratory
• QC/Drug levels-PK/Toxicology
• Pharmacogenetics
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Integration of
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expertise in clinical pharmac(olog)y in the framework of
Patient Care and Research
Identification – In depth analysis mechanisms – Translation to patient care
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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
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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
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