The link between nonclinical and clinical testing are
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 • 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
QTc in Man (2)
Effects on HERG in HEK 293 Cells 120 Percentage Change 100 80 E-4031 Cisapride Terfenadine Terodiline Verapamil 60 40 20 0 0. 01 0. 1 1 10 1000 Concentration (n. M) 10000
Dofetilide
Therapeutic Window and Td. P Webster, Leishman & Walker (2002) Towards a drug concentration effect relationship for QT prolongation and torsades de pointes. Current Opinion in Drug Discovery & Development
H 1 Antagonists Terfenadine Astemizole (desmethyl astemizole) Ebastine Cetirizine h. ERG IC 50 IKr IC 50 Unbound (n. M) Plasma Conc (n. M) 9. 4 - 213 150 - 1000 0. 1 – 9. 0 0. 9 – 26 Margin 1 1. 5 - 1000 0. 2 – 2. 6 0. 3 300 108, 000 3. 8 – 5. 1 56 59 23 1 331 1300 Fexofenadine 13, 100 – >5, 000 348 38 23, 000 astemizole terfenadine>>cetirizine fexofenadine ebastine Differences HERG/IKr potency, Plasma concentrations and PK interaction data taken into account
HERG – Predictive Value
Effect in Canine Purkinje Fibre
Anesthetized Dog - MAPD 150 bpm Percentage Change 40 20 E-4031 Cisapride Terfenadine Terodiline Verapamil 0 0. 01 0. 1 1 10 1000 Plasma Concentration (Unbound; n. M) 10000
AV Blocked Dog
Effect in Repolarization and Proarrhythmia Model
Correlation Between Models - Cisapride
Correlation Between Models - Terodiline
Correlation Between Models - Terfenadine
Weight of Evidence – Predictive Value
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 Td. P 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ABPI Data set Compounds were categorised as: 1 Class III antiarrhythmics 2 Withdrawn from market for QT or Torsade de Pointes 3 Strong evidence for Torsade de Pointes 4 Clinical evidence is weak or absent
HERG Selectivity of 5 -fold attrition 32% 68% Y Compounds in groups 1 -3? N 95% 5% Y N Missed opportunities Selectivity for human exposure vs HERG >5 -fold
HERG Selectivity of 10 -fold 20% 80% Y 95% N 5% Y Compounds in groups 1 -3? N
HERG Selectivity of 30 -fold 12% 88% Y Compounds in groups 1 -3? N Y 90% N 10%
HERG Selectivity of 100 -fold 8% 92% Y Compounds in groups 1 -3? N Y 60% N 40%
HERG Selectivity of 1000 -fold 4% 96% Compounds in groups 1 -3? 15% 85%
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 Threshold for IKr (90 n. M) Cmax vs. IKr selectivity 2 or 15 -fold 1 o pharmacology 2 n. M
Impact of drug interactions Cyp 3 A 4 inhibitor increases t 1/2 resulting in drug accumulation. Pharmacological selectivity is eroded further. Threshold for IKr 1 o pharmacology
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 Td. P • 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 council Derek Leishman Rob 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 drug development 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
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