C Mike Perkins MD Pfizer Global Research & Development
description
Transcript of C Mike Perkins MD Pfizer Global Research & Development
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
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
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
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
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
Dofetilide
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
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
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Withdrawn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
Effect in Canine Purkinje Fibre
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)
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
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
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)
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)
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)
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
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
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
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
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
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
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%
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%
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%
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%
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
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
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.
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
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
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.
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
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
Thank you