Personalised Medicine: Beyond the buzzword Dr. Oscar Della Pasqua C C linical Pharmacology...
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Transcript of Personalised Medicine: Beyond the buzzword Dr. Oscar Della Pasqua C C linical Pharmacology...
Personalised Medicine: Personalised Medicine: Beyond the buzzwordBeyond the buzzword
Dr. Oscar Della PasquaDr. Oscar Della Pasqua
CClinical PharmacologyGlaxoSmithKline, United Kingdom
OutlineOutline
- Does ‘personalised’ effectively mean the same for clinicians, patients and industry?
- What are the implications for drug development ?
Effectiveness – integrated measure(s) of efficacy and safety
shift in paradigm from ‘one dose fits all’
shift in paradigm from ‘one endpoint fits all’
shift in paradigm from ‘large, non-enriched trials’
- Model-based approach to integrate data:
right dose, right patient, right methods
- Conclusions
‘Clinical Reality….We’ve got a new wonder drug! - But I wonder what it will do for you.We’ve got a new wonder drug! - But I wonder which dose to prescribe.
All patients with same diagnosis
1
2
Responders and patients not predisposed to toxicity
Non-responders or toxic
responders
Treat with alternative drug
Treat with most suitable dose
Treatment Decisions Treatment Decisions
Biomarkers of Drug ResponseBiomarkers of Drug Response
Clinical Relevance - Predictive ValueClinical Relevance - Predictive ValueUtility of the information/biomarkerUtility of the information/biomarker
Examples– ErbB-2 over-expression and response to Herceptin
– ALOX5 promoter in asthma
– CrCL
– Bone marrow density
Variation VariationY YY YN N N N
Res
pon
se YY
N N
Best Good Poor Not a biomarker
Co
nc
(nm
ol/
L)
Hours
Number of functionalCYP2D6 genes
0
0
1
2
3
13
30
60
0 24 48 72
CYP2D6 - Polymorphisms CYP2D6 - Polymorphisms • Number of functional CYP2D6 alleles (0 - 13) determines concentrations of nortriptyline. 2 allele patients had greater clearance than 1 or 0 allele patients.
• Lack of efficacy in CYP2D6 x 13 patients
Nortriptyline 25 mg dose
Clinical relevance of CYP2D6Clinical relevance of CYP2D6Nortriptyline dosing recommendation in Europe Nortriptyline dosing recommendation in Europe
Clinical Relevance of CYP2D6 Clinical Relevance of CYP2D6 Strattera - No Dosing AdjustmentStrattera - No Dosing Adjustment
Initial approval 2002, USA
Are the answers to personalised medicine really here or does one need to look beyond?
(Am J Psychiatry 2002; 159:122–129)
C
G A T G G A A T
A G C C T A C A T A C T A A
A G
T A
A C C A T T A A G G T
T G T
A C T A
A C A C
G A A C
G C G A
C T G T
G A C C T T C A A T G G A T T A A G C C
A GA
AT
A A T A A C C T A T
T T G
T C A A A G T A C
G A G C A A T A G T
A
T A C G A T G
Consider Genetics
Epidemiology / Genetics / Clinical Pharmacology
Disease / Pharmacokinetics / Pharmacodynamics
Can one predict the impact of variability Can one predict the impact of variability or noise in drug effect with a single or noise in drug effect with a single
marker?marker?
What do you see when you have spent 8 months designing a sports car?
D
D H E R B A L S
C O M E D I C A T I O N S U
E G
T M
A B O D Y W E I G H T
P R T
R Y T A
O F R B
T A A O
E C N L
I T S I
G E N E T I C P O L Y M O R P H I S M S
B R O I
I S R E N Z Y M E S
N T G
D I S E A S E S E
I R E C E P T O R S
N S
T A R G E T S
Consider Intrinsic and Extrinsic Factors
Epidemiology / Genetics / Clinical Pharmacology
Disease / Pharmacokinetics / Pharmacodynamics
D
D H E R B A L S
C O M E D I C A T I O N S U
E G
T M
A B O D Y W E I G H T
P R T
R Y T A
O F R B
T A A O
E C N L
I T S I
G E N E T I C P O L Y M O R P H I S M S
B R O I
I S R E N Z Y M E S
N T G
D I S E A S E S E
I R E C E P T O R S
N S
T A R G E T S
Model-based Approaches for Prediction of ResponseModel-based Approaches for Prediction of Response
Epidemiology / Genetics / Clinical Pharmacology
Disease / Pharmacokinetics / Pharmacodynamics
BeSt study designBeSt study design• Retrospective, multi-centre, open • 509 patients with active RA enrolled in this study are
participants in a trial to test the effectiveness of different treatment strategies (BeSt- study)
• all patients have active disease according to ACR criteria, disease duration < 2 years
• 247 patients are treated with monotherapy MTX
Wessels et al. Arthritis Rheum.56:1765-75, 2007
BeST study: summaryBeST study: summary
205 RA patients
Active RA at baseline DAS 4.5
MTX 15 mg/week or 25 mg/week, folic acid 1 mg/day
RESPONSE 47% at 6 months
ADVERSE DRUG EVENTS 30%
DAS >2.4
DAS 2.4
Treatment outcome
Host
Disease Environment
Genes
Drug
Disease activity scoreACR criteria
Health assessment questionnaireRadiographic score
agegenderhormonal statusco-morbidityethnicityprevious DMARD use
Life style e.g. smoking and dietsocial class
HLA-DRB1 alleles (shared epitope)PTPN22Cytochrome P450 enzymesCandidate genes
Disease durationdisease activityAnti-CCPrheumatoid factor
Factors influencing outcome
Measures to evaluate outcome
RFC
Folate pathway Folate pathway
46
62
80
46
66
88
50
77
100
Number of MTHFR 677C-1298A haplotype copies
MTHFR haplotype as factor for MTX response
good clinicalresponse
good clinicalimprovement
moderate clincalimrpovement
MTHFR testing maydetermine which RA patients will benefit from MTX
genetics contribute to MTX treatment outcome in RA
AMPD
ITPA
‘‘Adenosine release’ Adenosine release’
AMPD1 T-allele, ATIC CC genotype, ITPA CC genotype are 2-3 fold more likely to achieve good clinical response
Favor
able
geno
types
ITPA C
C
ATIC C
C
AMPD T
-alle
le
ITPA C
C + A
TIC C
C
AMPD T
-alle
le +
ITPA C
C
ATIC C
C + A
MPD T
-alle
le
all th
ree
favo
rable
over
all p
opula
tion
5058 60
6168
75
93
3726
4237
4143
4347
Good clinical response with MTX
at 6 months (%)
From associations with genes
to a predictive clinical tool
“MTX sensitive RA”
- Simple model
- validation in 2nd cohort
Current MTX pharmacogenetic researchCurrent MTX pharmacogenetic research
24 baseline variables believed
to influence RA disease state
and MTX drug response were
selected based on literature
Development of a predictive model of Development of a predictive model of clinical responseclinical response
RFC
AMPD
ITPA
17 SNPs in 13 genes involved in the MTX mechanism of action, purine and pyrimidine synthesis
Factors determining efficacy for Factors determining efficacy for individual MTX monotherapy individual MTX monotherapy
Baseline Variable Score
premenopausal1Gender Female
postmenopausal 1Male 0
Disease activity DAS at baseline 3.8 0DAS at baseline >3.8, but 5.1 3DAS at baseline >5.1 3.5
Immunological factors Rheumatoid factor negative and non-smoker 0Rheumatoid factor negative and smoker 1Rheumatoid factor positive and non-smoker 1Rheumatoid factor positive and smoker 2
Genetic factors MTHFD1 1958 AA genotype 1AMPD1 34 CC genotype 1ITPA 94 A- allele carrier 2ATIC 347 G-allele carrier 1Other genotypes 0
Baseline Variable Score
premenopausal1Gender Female
postmenopausal 1Male 0
Disease activity DAS at baseline 3.8 0DAS at baseline >3.8, but 5.1 3DAS at baseline >5.1 3.5
Immunological factors Rheumatoid factor negative and non-smoker 0Rheumatoid factor negative and smoker 1Rheumatoid factor positive and non-smoker 1Rheumatoid factor positive and smoker 2
Genetic factors MTHFD1 1958 AA genotype 1AMPD1 34 CC genotype 1ITPA 94 A- allele carrier 2ATIC 347 G-allele carrier 1Other genotypes 0
≤≤
Suggestions for clinical applicationSuggestions for clinical applicationof the modelof the model
Categories Clinical consequence
Scores ≥ 6 Low probability to respond to MTX monotherapy. Consider a combination strategy.
Scores < 6, but > 3.5
Scores ≤ 3.5 High probability to respond to MTX monotherapy Dose escalation to 25 mg/weekif necessary.
Intermediate probability to respond to MTX monotherapy. Evaluate after 3 months therapy.
Categories Clinical consequence
Scores ≥ 6 Low probability to respond to MTX monotherapy. Consider a combination strategy.
Scores < 6, but > 3.5
Scores ≤ 3.5 High probability to respond to MTX monotherapy Dose escalation to 25 mg/weekif necessary.
Intermediate probability to respond to MTX monotherapy. Evaluate after 3 months therapy.
Categories Clinical consequenceCategories Clinical consequence
Scores ≥ 6 Low probability to respond to MTX monotherapy. Consider a combination strategy.
Scores < 6, but > 3.5
Scores ≤ 3.5 High probability to respond to MTX monotherapy Dose escalation to 25 mg/weekif necessary.
Intermediate probability to respond to MTX monotherapy. Evaluate after 3 months therapy.
Scores ≥ 6 Low probability to respond to MTX monotherapy. Consider a combination strategy.
Scores < 6, but > 3.5
Scores ≤ 3.5 High probability to respond to MTX monotherapy Dose escalation to 25 mg/weekif necessary.
Intermediate probability to respond to MTX monotherapy. Evaluate after 3 months therapy.
Receiver Operating Curves (ROC)Receiver Operating Curves (ROC)
1,00,80,50,30,0
0,8
0,5
0,3
1,0
sensitivity
1- specificity
non-genetic model
pharmacogenetic modelPG Model:
True positive response 95% (36 out of 38)
True negative response 87% (62 out of 72)
Percentage of patients categorized: 60%
Non-genetic model
Percentage of patients categorised: 32%
Conclusions - BeSTConclusions - BeST
The chance to achieve clinical response with MTX
treatment is predictable in recent onset RA.
It is feasible to assist initial treatment decisions
to tailor therapy in RA patients according to their baseline criteria
(symptoms, signs and genotype)
D
D H E R B A L S
C O M E D I C A T I O N S U
E G
T M
A B O D Y W E I G H T
P R T
R Y T A
O F R B
T A A O
E C N L
I T S I
G E N E T I C P O L Y M O R P H I S M S
B R O I
I S R E N Z Y M E S
N T G
D I S E A S E S E
I R E C E P T O R S
N S
T A R G E T S
Model-based Approaches for Dose OptimisationModel-based Approaches for Dose Optimisation
Epidemiology / Genetics / Clinical Pharmacology
Disease / Pharmacokinetics / Pharmacodynamics
New Technologies – Old tools? New Technologies – Old tools? From Biomarker data to Treatment Decision
JAMA, 296 (12), 2006
Exposure Adverse Events
Effi
cacy
The concentration-response surface:What is the surface for a given population /patient group?
Where are you during development?
Multidimensional Diseases - Multiple Endpoints -
1. Migraine (4)
2. Alzheimers (2)
3. Acute Pain (3)
4. Lower Back Pain (3)
5. Sleep Disorders (3 or 6)
6. RA (4)
7. OA for symptom modif. (2)
8. Asthma, COPD (2)
9. ED (3)
10. Skin Aging (2)
11. Menopausal Symptoms (3)
12. Fracture Healing (2)
13. Acne (4)
14. Male Pattern Baldness (2)
15. Glaucoma (9)
16. Ophthalmology – dry eye (2)
17. Hepatitis B (up to 3)
18. Vaginal Atrophy (3)
19. Organ Transplantation (2)
20. Primary Biliary Cirrhosis (4)
21. BPH (2)
22. Multiple Sclerosis (2)
23. Epilepsy (3)
24. Vaccines (up to 23)
25. Operable Breast Cancer(with + auxiliary lymph nodes) (2)
26. Fibromyalgia (2-3)
Model-based risk assessment Model-based risk assessment
Model-based risk assessment Model-based risk assessment
Model-based Approaches:Model-based Approaches:Dosage strategy for enoxaparin
Observed vs. population predicted anti-Xa concentrations for the two-compartment model with CrCL and weight covariates in the model. Individual data points are shown as dots and the unity as a solid line
Three-dimensional surface showing the relationship between CrCL, weight and predicted Css. The surface shows how the Css changes with both weight and CrCL simultaneously
Feng et al (2007), Br J Clin Pharmacol 62:165–176
% C
ss <
0.5
UI/m
l%
Css
>1.
2 U
I/ml
% C
ss o
ut
of
ran
ge
(1, CrCL <30 ml min−1; 2, CrCL 30–50 ml min−1; 3, CrCL >50 ml min−1).
8.3 IU/ kh/h5.8 IU/kg/h5.0 IU/kg/h4.2 IU/kg/h
intensive care unit general medical unit
Model-based Dose RecommendationsModel-based Dose Recommendations
Barras et al. (2007) Clin Pharmacol Ther advance online publication doi:10.1038/sj.clpt.6100399
Sotalol in SVTSotalol in SVTP
roba
bilit
y of
Res
pons
e
Sotalol conc (ug/mL)
PK/PD relationship Effect of Age on Clearance
Probability of arrhythmia suppression in the 15 children with supraventricular tachycardia vs sotalol trough concentration under steady-state conditions and an 8-h dosing interval. Filled circles 6 neonates (28 days).
Age (years)
Sot
alol
ora
l Cle
aran
ce
(m
l/min
/kg)
Measured (closed diamonds) and model predicted oral sotalol clearance based on body weight (open diamonds). Median (solid line) and the 10th and 90th percentile (dashed line) of 1,000 simulated data sets.
Dose Dose RecommendationRecommendation
Black box plots and hatched bars indicate recommended dosing range. (A) Simulated sotalol trough concentrations (125 patients per group and dose level) for paediatric patients with supraventricular tachycardia. Lines indicate 50% and more than 95% efficacy. (B) Patient fraction with 50% and more than 95% probability of arrhythmia suppression. Arrowsindicate start and target doses.
Age-specific Dosing regimen for sotalol in children with SVT
SummarySummary
- Does ‘personalised’ effectively mean the same for clinicians, patients and industry?
- What are the implications for drug development ?
Effectiveness – integrated measure(s) of efficacy and safety
shift in paradigm from ‘one dose fits all’
shift in paradigm from ‘one endpoint fits all’
shift in paradigm from ‘large, non-enriched trials’
- Model-based approach to integrate data:
right dose, right patient, right methods
- Conclusions
Personalised Treatment: Delicate Balance Between Personalised Treatment: Delicate Balance Between Benefit and RiskBenefit and Risk
The greatest obstacle to discovery is not
ignorance, but the illusion of knowledge
by Daniel Boorstinby Daniel Boorstin