Joint Annual meeting 2005 AGAH-Club Phase I

Transcription

1 Joint Annual meeting 2005 AGAH-Club Phase I Early Drug Development Scientific and Regulatory challenges Strasbourg, March 17-18, 2005

2 Early drug development Scientific and Regulatory challenges QTc: Predictability, Science, Regulation Pierre Maison-Blanche, MD Hôpital Lariboisière MDSPS, Sanofi-Aventis, Ela Medical, Chiesi, GSK, Pfizer, AMPS, Cardionics, Jerini,..

3 .. NONE

4 Willem Einthoven

5 RECORDING THE ECG Leiden, c

6 François Dessertenne 1966

7 Individual QT/RR relation Continuous ECG monitoring Time matched analysis

8 Why individual QT/RR data?

9 QT Interval and Heart Rate Measured QT 0,500 0,450 0,400 0,350 0,300 0,250 0,200 0,4 0,5 0,6 0,7 0,8 0,9 1,0 1,1 1,2 1,3 1,4 1,5 RR Interval (s) QTo HR=100 HR=50

10 Rate Correction of the QT Interval Measured and Corrected QT 0,500 0,450 0,400 0,350 0,300 0,250 0,200 0,4 0,5 0,6 0,7 0,8 0,9 1,0 1,1 1,2 1,3 1,4 1,5 RR Interval (s) QTo QTlc HR=100 HR=50

11 QT Interval: sources of variation Technique of QT recording and measurement HEART RATE +++ Sympathetic and Parasympathetic activity (circadian) Gender (sex hormones) Age Electrolyte disorders (K +, Ca 2+, Mg 2+ ) Drugs (K + channel modulators,...) Diseases (cardiac, metabolic, endocrine, neurologic) Genetics

12 QT interval: sources of variation Gender Steeper slopes in females than in males Direct influences of sex hormones Stramba Badiale et al Eur Heart J 1997

13 QT interval: sources of variations Age Hopital Lariboisière 2001

14 Individual QT corrections QT msec RR msec

15 Individual QT/RR relations Couderc et al, Annals of Noninvasive Electrocardiology, 2005; 10 : QT/RR slope computed from QT-RR pairs from the 24-hour pool (5 pairs increments) 20 sets randomly selected from the pool at each number Standard deviation of α (slope) within the 20 estimates Max and Min values of α, identification of maximum QT error (msec), largest deviation between the 2 curves at any heart rates

16 Individual QT/RR relations ST of α decreases with the number of QT-RR pairs Maximum error for QT can reach 10 msec below 100 QT-RR pairs

17 Individual QT/RR relations Couderc et al, ANE 2005 Effect of heart rate ranges on models using 100 QT-RR pairs Smallest msec Largest msec, steps of 25 msec Standard deviation of slope α, 20 estimates

18 Individual QT/RR relations Model based on 100 QT-RR pairs and heart rate ranges between 60 and 100 bpm provides slope stability

19 Individual QT/RR relations Couderc et al, ANE 2005 Identification of the end of the T wave is dependent on the morphology of the T wave and on its amplitude as well Cut-off 0.3 mv (high and low T-wave amplitude) QT/RR relations based on low amplitude T waves are associated with a less stable regression model

20 QT hysteresis effect Non steady state Lande et al PACE 2000

21 QT hysteresis effect Steady state Lande et al PACE 2000

22 Individual QT corrections: look at numbers! After Malik

23 Pre Therapy QT/RR On Drug QT/RR Class III agent: reverse rate-dependence

24 QT Dynamicity Post Myocardial Infarction Biphasic pattern Extramiana et al Am J Cardiol 1999 Hopital Lariboisière 2000

25 Individual QT corrections a finger-print? QT/RR Mean Minimum Maximum Period ±0.19 Period ±0.020 Period ±0.018 Period ±

26 QT/RR α RR= RR=1030 RR=1020 RR= RR=1240 RR=1280 RR=1340 RR= Baseline 1 Baseline 2 Baseline 3 Baseline 4

27 A B QT/RR α RR4 (msec) Delta QT Delta RR y = -7E-05x R² = 0.30 y = 0.078x R² = 0.35

28 Continuous ECG monitoring?

29 Norman Holter

30 Norman Holter

31 Standard 12lead vs Holter12lead Electrocardiographic identification of drug-induced QT prolongation: assessment by different recording and measurement methods Nenad Sarapa et al, Annals of Noninvasive Electrocardiology, 2004; 9: Standard supine 12lead ECGs: ELI200, Mortara Instruments, 500 sps (2 msec) Holter 12lead: H12 recorder, Mortara Instruments, 180 sps (5.6 msec) Open label, non-randomized study: baseline (day-1), a single administration of 160 mg (day 1) and of 320 mg (day 2) 16 ECG time points from pre-dose to 22 hours after dosing

32 Standard12lead vs Holter12lead Sarapa et al, ANE 2004

33 SpiderView SD card 64, 128, 256 MB 85 g weight credit card size 2 leads, 12 leads calculated XYZ, 12 leads 10 electrodes Multiday, 1-4

34 PDY Moxifloxacin results Cardio-Renal FDA Advisory Board, May 29, 2003 (in press, CPT 2005) Endpoint Change vs placebo (msec) Holter Individual QT Ela devices, 200 sps

35 Holter 12lead Randomized, Placebo controlled, 4 parallel groups study Drug x (two doses), Placebo, Moxifloxacin 400 mg Continuous 12lead ECG monitoring using H12 recorder (Mortara Instruments) 12lead ECGs (10-second each), were extracted from the Holter recording system (XML file). Each time point consisted of a triplicate recording, 3 ECGs extracted within 5 minutes.

36 Holter 12lead Change From Baseline In ECG Parameters Treatment Mean diff vs placebo P-value Lower 95% CI Upper Change QTcB (msec) Moxifloxacin 400mg Change QTcF (msec) Moxifloxacin 400mg Change QTcN (msec) Moxifloxacin 400mg

37 Holter 12lead: limb roots

38 H12+ Digital Recorder Continuous, true 12-lead acquisition at up to 1000Hz Waveform Display Digital Patient ID Entry Electronic Event Marker Removable Compact Flash Card memory 64 MB 24 Hour 180Hz 128MB 48 Hour 180Hz 512 MB HiFi 24 Hour 1000Hz

39 Bedside configurations

40 Why time-matched ECG?

41 Time-matched ECG Long-term circadian variations Day-night comparison at identical HR (60 bpm) Murakawa et al Am J Cardiol 1992

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43 Circadian Variations 15 msec QT lengthening PKD 4532 Sub 001

44 QT Run in Placebo ECG/30sec Maximal change in QT interval Time matched ECG/30sec QT Drug Administration

45 THANK YOU