Infrastructure for Developing Pharmacogenomics · 5/13/2010 · Gualberto Ruaño, M.D., Ph.D. ......
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Gualberto Ruaño, M.D., Ph.D. Director of Genetics Research, Hartford Hospital Professor Adjunct, University of Puerto Rico Medical Sciences Infrastructure for Developing Pharmacogenomics Genotype-Guided Psychotropic Management at the Institute of Living 13 May 2010
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Transcript of Infrastructure for Developing Pharmacogenomics · 5/13/2010 · Gualberto Ruaño, M.D., Ph.D. ......
Gualberto Ruaño, M.D., Ph.D.Director of Genetics Research, Hartford Hospital
Professor Adjunct, University of Puerto Rico Medical Sciences
Infrastructure for Developing PharmacogenomicsGenotype-Guided Psychotropic Management at the Institute of Living
13 May 2010
Founded in 1822 on principles of “Moral Treatment”
Merged with Hartford Hospital in 1994
Ranked among the nation’s Top 20 psychiatric hospitals by U.S. News & World Report for 3rd consecutive year
Institute of Living at Hartford HospitalClinical and research achievements
Institute of Living at Hartford HospitalClinical and research achievements
The Olin Neuropsychiatry Research Center
The Burlingame Center for Psychiatric Research and Education
The Braceland Center for Mental Health and Aging
The Anxiety Disorders Center
The Laboratory of Personalized Health and Genetics Research Center
Genomas Inc.
DNA-Guided Psychotropic TherapyPresentations at American Psychiatric Assoc.
Genotype-Guided Psychotropic Therapy
APA Symposium: Mayo, IOL, Genomas
CYP Genotyping in Patients Treated
for Depression
Combinatorial CYP450 Genotyping
for Depressed Inpatients
2007
2008
2009
Longer Hospitalization Associated
with Combinatorial CYP450
Drug Metabolism Deficiencies 2010
HILOmet PhyzioType SystemConfiguration and Bioclinical Algorithms
NULL
Low Metabolic Reserve0 Reserve, 1 Alteration
DEFICIENT
Med Metabolic Reserve0.5 Reserve, 0.5 or 1 Alteration
FUNCTIONAL
High Metabolic Reserve1 Reserve, 0 Alteration
SUPRA
Ultra Metabolic Reserve1.5 Reserve, 0.5 or 1 Alteration
HILOmet Indices Metabolic Reserve
Metabolic Alteration
Allele Alteration
Gene Alteration
2D6 2C9 2C19 3 Genes
6 Chr. Loci
34 Alleles
PROPRIETARYPatent Pending
20 alleles 6 alleles 8 alleles
PHP
P O R T A L
P E R S O N A L I Z E D H E A L T H
2D6
2C9
2C19
HILOmet PhyzioType: Gene LociCombinatorial Independent Segregation
HILOmet PhyzioType SystemConfiguration and Bioclinical Algorithms
None
2C9
2D6
2C19
2D6
2C19
2C9
2C19
2C9
2D6
2C9
2C19
2D6
Single Gene
Alterations
46%
Double and
Triple Gene
Alterations
45%
No Gene
Alterations
9%
N=577LPH Patient
ReferralsNov. 2009
HILOmet Drug Metabolism ReservePsychiatric Patient Referrals to LPH (N=577)
8
HILOmet Drug Metabolism AlterationPsychiatric Patient Referrals to LPH (N=577)
9
HILOmet Allele and Gene AlterationPsychiatric Patient Referrals to LPH (N=577)
PhyzioType Reimbursement: ValueHILOmet: Psych Referrals vs. Cardiology
11
Ruaño, Goethe et al, Personalized Medicine 2008
PhyzioType Reimbursement: ValueHILOmet: Hospitalization Length of Stay
0 5 10 15 20
MeanSDN
6.33.4146
Hospitalization Days
01
02
03
04
0
# P
ati
en
ts
PhyzioType Reimbursement: Value
HILOmet: Hospitalization Length of Stay
13
PhyzioType Reimbursement: ValueHILOmet: LDL and Cardiometabolic Risk
15
LPH Laboratory of Personalized HealthPharmacogenetics Lab, Clinical Launchpad
Pioneering high complexity
pharmacogenetics laboratory +
clinical practice
Anchor for commercialization of
PhyzioType Systems throughout
New England and nationally
Referral Center for Institute of
Living + Mood Disorders Program
CT-wide distribution and
reimbursement agreement with
Clinical Lab Partners
Used by 92 Clinicians in 2009
293 Patients referred in 2009
820 PhyzioType tests in 2009
Reimbursement rate >95%
Licensed by CT Dept of Public
Health (#CL-0644)
CLIA certified and registered
(Clinical Laboratory Improvement
Amendments)
ID #07D1036625 CMS (Centers for
Medicare and Medicaid)
3 successful biannual inspections
(most recent March 2009)
53 patient service centers in CT
Subsidiary of Hartford Hospital
LABORATORY OF PERSONALIZED HEALTH
LPH
HILOmet PhyzioType SystemContinued Successful Clinical Adoption
0
500
1000
1500
2000
2500
Qtr 1 Qtr 2 Qtr 3 Qtr 4
Ordering Tests Patients Tests/ Tests/
Docs Ordered Tested Patient Doc
2008 Actual 44 339 124 2.7 7.7
2009 Actual 92 820 293 2.8 8.8
4 Qtrs to March '10 127 1211 432 2.8 9.5
2010 Projection 320 2400 800 2.8 7.5
0
500
1000
1500
2000
2500
Qtr 1 Qtr 2 Qtr 3 Qtr 4
Cumulative Test Volume by Quarter
2009 Actual 2010 Projected*
0
500
1000
1500
2000
2500
Qtr 1 Qtr 2 Qtr 3 Qtr 4
2008 Actual
Q1 is Actual
Drug
Intolerance or
Resistance
Empirical
Therapy
Monitor
Response
PhyzioType Clinical ApplicationsDrug GPS for DNA-Guided Medicine
Drug Intolerance or
Resistance Diagnosis
Diagnose innate metabolic
cause of drug intolerance
or resistance
Enable doctor to precisely
benchmark patient
Rule out confounders
(mental status, active or
sedentary lifestyle, diet)
P H Y Z I O T Y P E S Y S T E M S
Monitor
Response
PhyzioType Clinical ApplicationsDrug GPS for DNA-Guided Medicine
Select Therapy for
High Risk Patient
Improved
Compliance
P H Y Z I O T Y P E S Y S T E M S
Optimized TherapyPrescription according to
innate capacity of response
or risk of side effects
IF RESPONSE IS HIGH
AND RISK IS LOW:
Prescribe w. safeguard
IF RESPONSE IS LOW
AND RISK IS HIGH:
Consider alternative drugs
Pre-treat side effect
HILOmet PhyzioType SystemDNA-Guided Psychotropic Management
NEUROLEPTICS: Generic (Brand) & Drug Selection
HILOmet PhyzioType System: LPH1Case Report and Clinical Management Utility
Patient LPH1 is a 54-year Caucasian female with a
history of anxiety and delusions who manifested:
Intolerance, resistance to 18 psychotropic drugs
over a 5-year period (akathisia, insomnia)
Ruaño, Blair, Goethe et al, Connecticut Medicine 2007
2D6 2C9 2C19
__________________________________________________
_________________________________________________
HILOmet
Combinatorial
Genotype
HIGH
BIO-CLINICAL
CYPARRAY
DRUG
METABOLISM
HILOmet
*3 *1
HILOmet PhyzioType System: LPH1Case Report and Clinical Management Utility
Patient LPH1 is a 54-year Caucasian female with a
history of anxiety and delusions who manifested:
Intolerance, resistance to 18 psychotropic drugs
over a 5-year period (akathisia, insomnia)
Ruaño, Blair, Goethe et al, Connecticut Medicine 2007
2D6 2C9 2C19
*6 *6 *1 *3 *1 *2
__________________________________________________
_________________________________________________
HILOmet
Combinatorial
Genotype
HIGH
BIO-CLINICAL
CYPARRAY
DRUG
METABOLISM
HILOmet
*3 *1
HILOmet PhyzioType System: LPH1Multi-gene drug metabolism deficiency
2D6 2C9 2C19
*6 *6 *1 *3LPH1
_____________________________________________
*4 *6 *2 *3 *1 *1Brother
*1 *2
_____________________________________________
HILOmet PhyzioType System: LPH1Case Report and Clinical Management Utility
Combinatorial GenotypePopulation Prevalence
HIGH
BIO-CLINICAL
CYPARRAY
DRUG
METABOLISM
HILOmet
*3 *1
0
20
40
60
80
100
120
140
160
180
Num
ber
of
Patie
nts
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
Drug Metabolism Alteration
100
90
80
70
60
50
40
30
20
10
02.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0
100
90
80
70
60
50
40
30
20
10
0
Perc
enta
ge o
f P
atie
nts Drug Metabolism Reserve
Patient LPH1 is a 54-year Caucasian female with a
history of anxiety and delusions who manifested:
Intolerance, resistance to 18 psychotropic drugs
over a 5-year period (akathisia, insomnia)
Drug Sensitivity
Syndrome
Ruaño, Goethe et al, Connecticut Medicine 2007
26
PHP Personalized Health PortalPsychotropic Management: Patient LPH1
HILOmet PhyzioType System: LC5Case Report and Clinical Management Utility
Patient LC5 is a 58-year Caucasian man with a history
of depression who manifested:
Intolerance and resistance to Lexapro®, requiring
compounding drug, 1/50th standard dose, ~0.2 mg
__________________________________________________
2D6 2C9 2C19
_________________________________________________
HILOmet
Combinatorial
Genotype
HIGH
BIO-CLINICAL
CYPARRAY
DRUG
METABOLISM
HILOmet
*3 *1
HILOmet PhyzioType System: LC5Case Report and Clinical Management Utility
Patient LC5 is a 58-year Caucasian man with a history
of depression who manifested:
Intolerance and resistance to Lexapro®, requiring
compounding drug, 1/50th standard dose, ~0.2 mg
__________________________________________________
2D6 2C9 2C19
*1 *2a *1 *1
_________________________________________________
*2 *2
HILOmet
Combinatorial
Genotype
HIGH
BIO-CLINICAL
CYPARRAY
DRUG
METABOLISM
HILOmet
*3 *1
HILOmet PhyzioType System: LC5Case Report and Clinical Management Utility
Combinatorial GenotypePopulation Prevalence
HIGH
BIO-CLINICAL
CYPARRAY
DRUG
METABOLISM
HILOmet
*3 *1
0
20
40
60
80
100
120
140
160
180
Num
ber
of
Patie
nts
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
Drug Metabolism Alteration
100
90
80
70
60
50
40
30
20
10
02.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0
100
90
80
70
60
50
40
30
20
10
0
Perc
enta
ge o
f P
atie
nts Drug Metabolism Reserve
Patient LC5 is a 58-year Caucasian man with a history
of depression who manifested:
Intolerance and resistance to Lexapro®, requiring
compounding drug, 1/50th standard dose, ~0.2 mg
PHP Personalized Health PortalPsychotropic Management: Patient LC5
HILOmet PhyzioType System: AH1Case Report and Clinical Management Utility
Patient AH1 is a 27-year old Caucasian woman on
Prozac® and Wellbutrin® with a complaint of:
“All my meds fail after a few weeks”
(according to note from referring psychiatrist)
________________________________________________
_________________________________________________
HILOmet
Combinatorial
Genotype
2D6 2C9 2C19
HIGH
BIO-CLINICAL
CYPARRAY
DRUG
METABOLISM
HILOmet
*3 *1
HILOmet PhyzioType System: AH1Case Report and Clinical Management Utility
Patient AH1 is a 27-year old Caucasian woman on
Prozac® and Wellbutrin® with a complaint of:
“All my meds fail after a few weeks”
(according to note from referring psychiatrist)
________________________________________________
_________________________________________________
HILOmet
Combinatorial
Genotype
2D6 2C9 2C19
*1 *1 *1 *1 *1 *1
HIGH
BIO-CLINICAL
CYPARRAY
DRUG
METABOLISM
HILOmet
*3 *1
HILOmet PhyzioType System: AH1Case Report and Clinical Management Utility
Patient AH1 is a 27-year old Caucasian woman on
Prozac® and Wellbutrin® with a complaint of:
“All my meds fail after a few weeks”
(according to note from referring psychiatrist)
HIGH
BIO-CLINICAL
CYPARRAY
DRUG
METABOLISM
HILOmet
*3 *1
Combinatorial GenotypePopulation Prevalence
0
20
40
60
80
100
120
140
160
180
Num
ber
of
Patie
nts
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
Drug Metabolism Alteration
100
90
80
70
60
50
40
30
20
10
02.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0
100
90
80
70
60
50
40
30
20
10
0
Perc
enta
ge o
f P
atie
nts Drug Metabolism Reserve
CVDDiabetesMetSyn
Central Nervous System
Appetite
Metabolic
6weeks
TG
Blood
Glucose
Energy Use
Start
Rx
Psychotropic Metabolic Side Effects Second Generation Antipsychotics
35
LEPR
Leptin
Receptor
PhysioGenomics of PIMS: RisperidoneDiscovery from Side Effect Spectrum: Weight
_______________________________
NPY5R
Neuropeptide
Y receptor Y5
Ruaño, Goethe, de Leon, Molecular Psychiatry, 2007
20 40 60 80 100 120 140 160
0.0
0.2
0.4
0.6
LEPR rs8179183
p = 0.000987805 r^2 = 11.3%
Ma
rker
Fre
qu
en
cy
20 40 60 80 100 120 140 160
0.0
0.2
0.4
0.6
PON1 rs705381
Ma
rker
Fre
qu
en
cy
20 40 60 80 100 140
0.00.2
0.40.6 LEPR rs8179183
p = 0.000987805
Marke
r Frequ
ency
20 40 60 80 100 120 140 160
PON1 rs705381
p = 0.0011838
Marke
r Frequ
ency
20 40 60 80 100 120 140 160
NPY5R rs6837793
p = 0.00238441
Marke
r Frequ
ency
NPY5R rs6837793
Ma
rker
Fre
qu
en
cy
Ma
rker
Fre
qu
en
cy
_______________________________
36
PIMS Total Genome Discovery: WaistHigh Resolution Genomic Learning
Sco
re:
-10*l
og
10(p
-valu
e)
Gene 1
Gene2Gene 4 Gene 3
Ge
4
37
PhyzioType Reimbursement: Value PIMS: Patients in BEST vs. WORST DRUG
PhyzioType System Predictions and Observed Clinical Endpoints for 3 AAPs:
233 patients on Risperdal®, 227 on Seroquel®, and 114 on Zyprexa®
mean w
ais
t
80
85
90
95
100
105
110
115
quetiapine best worst
227 70 85
mean w
ais
t
80
85
90
95
100
105
110
115
risperidone best worst
233 61 83
mean w
ais
t
80
85
90
95
100
105
110
115
olanzapine best worst
114 43 26
mean w
ais
t
80
85
90
95
100
105
110
115
all best worst
922 174 194
ON BEST WORST
233
WA
IST
(c
m)
Risperdal®
mean w
ais
t
80
85
90
95
100
105
110
115
quetiapine best worst
227 70 85
mean w
ais
t
80
85
90
95
100
105
110
115
risperidone best worst
233 61 83
mean w
ais
t
80
85
90
95
100
105
110
115
olanzapine best worst
114 43 26
mean w
ais
t
80
85
90
95
100
105
110
115
all best worst
922 174 194
227
ON BEST WORST
WA
IST
(c
m)
Seroquel®
mean w
ais
t
80
85
90
95
100
105
110
115
quetiapine best worst
227 70 85
mean w
ais
t
80
85
90
95
100
105
110
115
risperidone best worst
233 61 83
mean w
ais
t
80
85
90
95
100
105
110
115
olanzapine best worst
114 43 26
mean w
ais
t
80
85
90
95
100
105
110
115
all best worst
922 174 194 114
ON BEST WORST
WA
IST
(c
m)
Zyprexa®
61 83 70 85 43 26
38% 23%31% 37%26% 36%
Acknowledgements Consortium Collaborators and Grant Support
Harold Schwartz MD Bonnie Szarek RN
John Goethe MD Steve Woolley PhD
Godfrey Pearlson MD Charles Calley PhD
Lisa Namerow MD Vincent Calhoun PhD
Jose de Leon, MD
Margaret Susce, RN
Andreas Windemuth PhD Krystyna Gorowski
Richard Seip PhD David Villagra
Bruce Bower MD Kali Bogaard
Mohan Kocherla Teresa Giuliano
Supported by Grants
5 R44 MH 073291-04
2 R44 MH 075481-03
LPH
39
DNA-Guided Medicine: Drug SelectionPhyzioTypeTM Systems for Drug Management
P H Y Z I O T Y P E S Y S T E M S
SNP Array
Assay
233
202
126 2
192
227
145
29 26 215
225
238
21 72 40 169
55 81 58 149
110
74 50 121
104
54 200
218
168
241
105
214
148
191
80 132
216
16 34 70
CR
-1 C2
SB
1278
9
SB
1501
SB
1825 C3
C1
SB
1541
SB
1727
SB
1461
SB
1278
1
SB
3039
Bioclinical
Algorithm
Physician
Portal
Patient
is here
Ranking Drug Response
HILOmet PhyzioType System: LPH2Case Report and Clinical Management Utility
Patient LPH2 is a 59-year Caucasian woman with a
history of major mood disorder who manifested:
Failure to respond to many antidepressants
despite ability to tolerate high doses.
2D6 2C9 2C19
________________________________________________
_________________________________________________
HILOmet
Combinatorial
Genotype
HIGH
BIO-CLINICAL
CYPARRAY
DRUG
METABOLISM
HILOmet
*3 *1
HILOmet PhyzioType System: LPH2Case Report and Clinical Management Utility
Patient LPH2 is a 59-year Caucasian woman with a
history of major mood disorder who manifested:
Failure to respond to many antidepressants
despite ability to tolerate high doses.
2D6 2C9 2C19
DUP *2a *3 *3
________________________________________________
_________________________________________________
*1 *1
HILOmet
Combinatorial
Genotype
HIGH
BIO-CLINICAL
CYPARRAY
DRUG
METABOLISM
HILOmet
*3 *1
42
PHP Personalized Health PortalPsychotropic Management: Patient LPH2
NEED DRUG SELECTION TABLE
HILOmet PhyzioType System: LN1
Adolescent Psych: New Rx, Hx Side Effects
LN1, 14-year old Caucasian adolescent, currently not
on psychotropics. Hx. of severe reaction to Celexa®.
Psychiatrist is considering Wellbutrin® or atypical
antipsychotic.
2D6 2C9 2C19
*4 *41 *1 *1 *1 *2
__________________________________________________
_________________________________________________
HILOmet
Combinatorial
Genotype
HIGH
BIO-CLINICAL
CYPARRAY
DRUG
METABOLISM
HILOmet
*3 *1
HILOmet PhyzioType System: LC5Case Report and Clinical Management Utility
Patient LC5 is a 58-year Caucasian man with a history
of depression who manifested:
Intolerance and resistance to Lexapro®, requiring
compounding drug, 1/50th standard dose, ~0.2 mg
__________________________________________________
2D6 2C9 2C19
*1 *2a *1 *1
_________________________________________________
*2 *2
HILOmet
Combinatorial
Genotype
HIGH
BIO-CLINICAL
CYPARRAY
DRUG
METABOLISM
HILOmet
*3 *1
HILOmet PhyzioType SystemCT Market Growth + Clinical Adoption
Increased confidence in clinical management
Confident in validity and utility of results
Interpretation helpful in optimizing clinical outcomes
Incorporate DNA guided systems into clinical practice
Positive patient feedback in regards to results
Most useful in the clinically complex patient
Survey of 24 Clinician Users
% Respondents
Agree Strongly*
75%
96%
67%
84%
67%
92%
*Scores of 4 or 5
in 5 point scale
