c mike perkins md pfizer global research & development
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The link between non-clinical and clinical testing ~ are non-clinical tests predictive of clinical effects?. C Mike Perkins MD Pfizer Global Research & Development. 31-3753. Outline. Based on standard agents with known effects on QT and arrhythmia Principal target - HERG/IKr - PowerPoint PPT PresentationTRANSCRIPT
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The link between non-clinical and clinical
testing ~ are non-clinical tests predictive of clinical effects?
C Mike Perkins MDPfizer Global Research & Development
31-3753
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Outline
• Based on standard agents with known effects on QT and arrhythmia
• Principal target - HERG/IKr• Safety margins• Are all HERG blockers the same?
– repolarisation assays– in vivo evaluations– Proarrhythmia
• Pharmacokinetics and drug-drug interactions
• Integrated risk assessment
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QTc in Man
0 500 1000 1500 2000 2500 3000 3500 40000
30
60
90
Ch
an
ge
in Q
Tc
(ms)
Concentration (ng/ml)
dofetilide terodiline terfenadine cisapride sotalol
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QTc in Man (2)
0 5 10 150
30
60
90
Ch
an
ge
in Q
Tc
Concentration Change (as multiples of lowest conc.)
dofetilide terodiline terfenadine cisapride sotalol
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0.01 0.1 1 10 100 1000 10000
0
20
40
60
80
100
120 E-4031
Cisapride Terfenadine Terodiline Verapamil
Per
cent
age
Cha
nge
Concentration (nM)
Effects on HERG in HEK293 Cells
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Dofetilide
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Therapeutic Window and TdP
Webster, Leishman & Walker (2002) Towards a drug concentration effect relationship for QT prolongation and torsades de pointes. Current Opinion in Drug Discovery & Development
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H1 Antagonists
hERG IC50(nM)
IKr IC50(nM)
Unbound Plasma Conc(nM)
Margin
Terfenadine 9.4 - 213 150 - 1000
0.1 – 9.0 1
Astemizole
(desmethyl astemizole)
0.9 – 26
1
1.5 - 1000
0.2 – 2.6 0.3
Ebastine 331 300 3.8 – 5.1 59Cetirizine 1300 108,000 56 23Fexofenadine 13,100 –
23,000>5,000 348 38
astemizoleterfenadine>>cetirizinefexofenadineebastine
DifferencesHERG/IKr potency, Plasma concentrations and PK interaction data taken into account
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HERG – Predictive Value
Antiarrhythmics
Withdrawn
Frequent TdP
Infrequent TdP
No Tdp
0 20 40 60 80 100
Percentage of Compounds Tested in HERG
No Signal Weak Signal Moderate Signal Strong Signal
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Effect in Canine Purkinje Fibre
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Anesthetized Dog - MAPD 150bpm
0.01 0.1 1 10 100 1000 10000
0
20
40 E-4031 Cisapride Terfenadine Terodiline Verapamil
Perc
en
tag
e C
han
ge
Plasma Concentration (Unbound; nM)
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AV Blocked Dog
Compound Incidence of TdP
Dose 1 Dose 2 Dose 3 Dose 4
E-4031 1/5 4/4 NT NT
Cisapride 0 1/5 3/4 0/1
Terfenadine 0 0 1/5 0/4
Terodiline 0 0 0 2/5
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Effect in Repolarization and Proarrhythmia Model
RM
P
AM
P
Vm
ax
AP
D50
AP
D90
MA
PD
TdP
-60-40-20
020406080
100120 E-4031
Cisapride Terfenadine Terodiline Verapamil
Per
cent
age
Cha
nge
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Correlation Between Models - Cisapride
0.01 0.1 1 10 100 1000 10000
0
20
40
60
80
100
120 QTc Prolongation HERG Inhibition Purkinje Fibre APD90 Prolongation MAPD Prolongation
Per
cent
age
Ch
ang
e
Concentration (nM)
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Correlation Between Models - Terodiline
0.01 0.1 1 10 100 1000 10000
0
20
40
60
80
100
120 QTc Prolongation HERG Inhibition Purkinje Fibre APD90 Prolongation MAPD Prolongation
Per
cent
age
Ch
ang
e
Concentration (nM)
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Correlation Between Models - Terfenadine
0.01 0.1 1 10 100 1000 10000
0
20
40
60
80
100
120 QTc Prolongation HERG Inhibition Purkinje Fibre APD90 Prolongation MAPD Prolongation
Per
cent
age
Ch
ang
e
Concentration (nM)
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Weight of Evidence – Predictive Value
Antiarrhythmics
Withdrawn
Frequent TdP
Infrequent TdP
No Tdp
0 20 40 60 80 100
Percentage of Compounds Tested in HERG
No Signal Weak Signal Moderate Signal Strong Signal
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Relative HERG inhibitory potency
Webster, Leishman & Walker (2002) Towards a drug concentration effect relationship for QT prolongation and torsades de pointes. Current Opinion in Drug Discovery & Development
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Therapeutic Window and TdP
Webster, Leishman & Walker (2002) Towards a drug concentration effect relationship for QT prolongation and torsades de pointes. Current Opinion in Drug Discovery & Development
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ABPI Data set
• Literature search on 95 drugs– HERG/IKr data– Action potential data– In vivo QT data– Free plasma drug levels following
therapeutic use
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ABPI Data set
Compounds were categorised as:
1 Class III antiarrhythmics2 Withdrawn from market for QT or
Torsade de Pointes3 Strong evidence for Torsade de
Pointes4 Clinical evidence is weak or absent
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HERG Selectivity of 5-fold
8 (erythromycin, amiodarone, sparfloxacin, procainamide, grepafloxacin, domperidone,
haloperidol and bepridil)
17
19
1
(verapamil)
Compoundsin groups 1-3?
Y
Y
N
N
Selectivity for human exposure vsHERG >5-fold
32% 68%
95% 5%
attrition
Missed opportunities
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HERG Selectivity of 10-fold
5 (erythromycin, amiodarone, bepridil, sparfloxacin and
grepafloxacin)
20
19
1
(verapamil)
Compoundsin groups 1-3?
Y
Y
N
N
20% 80%
95% 5%
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HERG Selectivity of 30-fold
3 (erythromycin, amiodarone and
bepridil)
22
18
2
(verapamil, cibenzoline)
Compoundsin groups 1-3?
Y
Y
N
N
12% 88%
90% 10%
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HERG Selectivity of 100-fold
Compoundsin groups 1-3?
Y
Y
N
N
2 (erythromycin and amiodarone)
23
12
8
(cibenzoline, imipramine, tedisamil ebastine, fexofenadine, olanzapine,
tamoxifen and verapamil)
8% 92%
60% 40%
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HERG Selectivity of 1000-fold
1 (amiodarone)
24
3
20
(amlodipine, cetirizine, chlorpheniramine, ciprofloxacin,
diltiazem, diphenhydramine, quetiapine, mibefradil,
ketoconazole, cibenzoline, imipramine, tedisamil ebastine,
fexofenadine, olanzapine, tamoxifen and verapamil)
Compoundsin groups 1-3?
96%4%
85%15%
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Conclusions
• HERG/IKr data alone is a remarkably good predictor of QT risk
• Smaller the TI the higher the risk• Power of non-clinical studies are greatly
increased with native tissue and in vivo data– Verapamil would be a true negative
• What is an appropriate TI?– Small TI (5-fold) identifies 68% ‘clinical actives’, but
32% false negatives and only 5% false positive– High TI (1000-fold) identifies 96% ‘clinical actives’,
only 4% false negatives, but 85% false positive
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Importance of PK on selectivity
1
10
100
0 24 48 72 96 120
Time (h)
Co
nc
en
tra
tio
n (
nM
)
1o pharmacology
2nM
Threshold for IKr (90 nM)
Cmax vs.IKr selectivity 2 or 15-fold
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Impact of drug interactions
1
10
100
1000
0 24 48 72 96 120
Time (h)
Co
nce
ntr
atio
n (
nM
)
1o
pharmacology
Threshold for IKr
Cyp 3A4 inhibitor increases t1/2 resulting in drug accumulation. Pharmacological selectivity is eroded further.
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Summary & Conclusions (1)
• Drugs associated with arrhythmia can give large concentration dependent changes in QTc
• Correlation exists between HERG potency and plasma concentrations associated with QT prolongation and TdP
• Therapeutic ratio can be determined and appears to correlate with the prevalence of cardiac arrhythmias
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Summary & Conclusions (2)
• Not all HERG blockers are the same– Other ion channel effects can be important– Additional effects may modulate risk of
arrhythmia• Plasma concentrations obviously are important
– Need to appreciate the impact of variability in plasma concentrations
– Drug-drug interactions can be very important as these influence safety margins
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Summary & Conclusions (3)
• Non-clinical assays can guide clinical QT studies by predicting the concentrations and circumstances under which QT prolongation and arrhythmia might occur, thus highlighting particular questions to be addressed.
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Acknowledgements
Pfizer QT advisory councilDerek LeishmanRob Wallis
Reference: Redfern, Carlsson, Davis et al
Relationships between preclinical cardiac electrophysiology, clinical
QT interval prolongation and Torsade de Pointes for a broad range
of drugs: evidence for a provisional safety margin in drugdevelopment
Cardiovascular research 58(2003) 32-45
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ICH
The Sixth International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use New Horizons and Future
Challenges
Osaka International Convention Center, Osaka, Japan
November 12-15 2003
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Thank you