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Withdrawn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