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Cardiac Safety Assessment: Screening for Drug-Induced Ventricular Arrhythmias by Joseph C. Randall, Ph.D. Director, Drug Development MDS Pharma Services.

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Presentation on theme: "Cardiac Safety Assessment: Screening for Drug-Induced Ventricular Arrhythmias by Joseph C. Randall, Ph.D. Director, Drug Development MDS Pharma Services."— Presentation transcript:

1 Cardiac Safety Assessment: Screening for Drug-Induced Ventricular Arrhythmias by Joseph C. Randall, Ph.D. Director, Drug Development MDS Pharma Services

2 Background A number of non-cardiovascular drugs withdrawn from the US market due to reports of sudden cardiac death, arrhythmias and QT-interval prolongation: Terfenadine (Seldane) - 21 deaths in UK (51% cardiac related) – withdrawn in 1997 after approval of Fexofenadine Sertindole – 27 deaths in US (59% cardiac related)- 1.3% of clinical trial patients – voluntary withdrawal in 1998 Cisapride (Propulsid) - 34 cases of Torsades and 23 cases of QT prolongation, 4 deaths and 16 resuscitated from 1993 to 1996 (US) – voluntary withdrawal in July, 2000 QT prolongation has been reported for older tricyclic antidepressants (Amitriptyline/Elavil & Imipramine), fluorquinoline antibiotics (Moxifloxacin and Grepafloxacin) and some opioids (Methadone, LAAM)

3 Background QT-interval prolongation was noted in the clinic Patch clamp methods were used to look at current flow through different ion channels –I Kr identified The hERG gene encodes the alpha-subunit of a delayed rectifying potassium channel (I Kr )- major pore forming subunit –involved cardiac repolarization I kr is a common target for drugs that  QT interval, but Na, Ca and other K-channels are also involved in heart conductance Bottom Line: QT-interval prolongation is a biomarker for increased risk of Ventricular Arrhythmias

4 Ion Channels Involved in Cardiac Action Potentials Ref # 1

5 What is Torsade de Points (TdP)? Note: Intravenous dose of Haloperidol, ICU patient, ~170 mg in 24 hours Ref # 2

6 What Kind of Drugs Can Induce QT-Interval Prolongation? Comprehensive list  Ref # 3

7 What is the Relative Risk of TdP? Ref # 3

8 Regulatory Response FDA recommended removal of Terfenadine containing products from the market in 01/1997 FDA issued warning letter to Doctors about cardiac safety of Cisapride Post-marketing surveillance became more important – Medwatch reporting system Safety pharmacology guidances were approved to look at cardiovascular, respiratory and CNS side- effects of drug candidates –ICH S7A and S7B Screening for QT prolongation is now an integral part of drug development (lead optimization to clinical)

9 Cisapride Story Drug to increase gastrointestinal (GI) motility Over 5.4 million prescriptions in 1996 (US) 34 patients TdP, 23 long QT 1993-1996 Cardiotoxicity reported when used with Ketoconazole and/or Erythromycin Case report of 8-year old girl–intensive care Drug withdrawn from US market –July, 2000 Ref # 4, 5

10 Drug Interactions Leading to QT  Ref # 4

11 HERG Inhibition by Cisapride Ref # 6

12 Lessons Learned Drug-drug interactions were a major risk factor in the cardiac toxicity of Terfenadine and Cisapride: Inhibition of Drug Metabolism or Clearance (e.g. Cytochrome P450 3A4 inhibitors-ketoconazole, grapefruit in diet) Concomitant medications that increase the QT interval (Erythromycin) Cannot predict QT prolongation by structure alone New drug safety testing guidelines were needed to protect patients from cardiac arrhythmias Mechanism of Cisapride-induced cardiotoxicity was proposed by Dr. Arthur Brown (1997)- Chantest Inc.

13 Risk Factors for Arrhythmias Age & Gender (F>M) Bradycardia (slow heart rate) Hypokalaemia and Hypomagnesaemia Atrioventricular Block (AV) Cardiac Disease or Hereditary Long QT Metabolic or Endocrine Disorders Drug Interactions (P-450 inhibitors)

14 Current Testing Guidelines hERG channel testing of new drug candidates is mandatory (ICH S7B)- HTS is available Cardiovascular safety testing in animals is also required (ICH S7B)-telemetry preferred A clinical trial is required to evaluate CV effects of systemically administered drugs- called “thorough QT study” (ICH E14)- concurrent or prior to Clinical Phase IIb

15 Design of Cardiovascular Screening Studies in Animals Telemeterized dogs are the animal model of choice – also monkeys and minipigs Positive control or reference compounds CV monitoring to bracket drug accumulation & elimination phases,T max,, t 1/2 QT-Interval is corrected for heart rate (QT c ) Plot QT c versus [drug] in plasma Crossover design is often better than parallel

16 Estimation of CV Safety Margins Ref # 7

17 Canine Purkinje Fiber Assay Ref # 8

18 Conclusions Many drugs that  QT are still on the market hERG potency does not predict risk of TdP I recommend Rabbit Purkinje fiber assay to understand multiple ion channel effects ICH 7B requires and integrated assessment of ion channel, action potential duration, and in- vivo ECG data-case by case discussion w/FDA Thorough QT trial needed prior to Phase IIb

19 Resources HTS Screening for hERG channel inhibition – Molecular Devices Inc., IonWorks Quattro Purkinje Fiber Assay (rabbits) – Chantest Inc. “Thorough QT Trials” (ICH E14) are routinely conducted at MDS Pharma Phase I clinics (see Cardiac Safety brochure)  over 100 trials Safety Pharmacology Testing is offered in our state of the art Toxicology facility in Lyon, France (brochure) Consulting & Central Cardiac Services at MDSPS List of drugs that prolong QT-

20 References 1) Brown, A.M. and Rampe, D. (2000). Drug-Induced QT Syndrome: Is HERG the Root of All Evil. Pharmaceutical News 7, 15-20. 2) Wilt, J.L., Minnema, A.M, Johnson, R.F. and Rosenblum, A.M. (1993). Torsade de Pointes Associated with the use of Intravenous Haloperidol. Ann. Intern. Med. 119(5): 391-394. 3) Yap, Y.G. and Camm, A.J. (2003). Drug induced QT prolongation and torsade de pointes. Heart 89: 1363-1372. 4) Pettignano, R., Chambliss, C.R., Darsey, E., Heard, M. and Clark, R. (1996). Cisapride-Induced Dysrthmia in a Pediatric Patient Receiving Extracorporeal Life Support. Crit. Care Med. 24(7): 1268-1271. 5) Wysowski, DK. and Bacsanyi, J. (1996). Cisapride and Fatal Arrhythmia. N Engl. J. Med. 335 (4), 290-291.

21 References 6) Rampe, D., Roy, M-L, Dennis, A., Brown, A. (1997). A Mechanism for the Proarrhythmic Effects of Cisapride (Propulsid): High Affinity Blockade of the Human Cardiac Potassium Channel HERG. FEBS Letters 417, 28-32 7) Katchman, A.N. et al., (2002). Influence of Opioid Agonists on Cardiac Human Ether-a-go-go related Gene K + Currents. J. Pharmacol. Exp. Ther. 303(2): 688-694. 8) Gintant, G., Limberis, J., McDermott, J., Wegner, C., Cox, B. (2001). The Canine Purkinje Fiber: An in Vitro Model System for Acquired Long QT Syndrome and Drug-Induced Arrhythmogenesis. J. Cardiov. Res. 37(5), 607-618.

22 ICH Guidance Documents S7A Safety Pharmacology Studies for Human Pharmaceuticals (2001) S7B Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceutical (2005) E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non- Antiarrhythmic Drugs (2005)

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