Cardiac Safety Assessment: Screening for Drug-Induced

Ventricular Arrhythmias

by

Joseph C. Randall, Ph.D.Director, Drug Development

MDS Pharma Services

Background A number of non-cardiovascular drugs withdrawn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Terfenadine (Seldane) - 21 deaths in UK (51% cardiac related) – withdrawn in 1997 after approval of Fexofenadine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)

Background QT-interval prolongation was noted in the clinic Patch clamp methods were used to look at current

flow through different ion channels –IKr identified The hERG gene encodes the alpha-subunit of a

delayed rectifying potassium channel (IKr)- major pore forming subunit –involved cardiac repolarization

Ikr 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

Ion Channels Involved in Cardiac Action Potentials

Ref # 1

What is Torsade de Points (TdP)?

Note: Intravenous dose of Haloperidol, ICU patient, ~170 mg in 24 hoursRef # 2

What Kind of Drugs Can Induce QT-Interval Prolongation?

Comprehensive list www.torsades.orgRef # 3

What is the Relative Risk of TdP?

Ref # 3

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)

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

Drug Interactions Leading to QT

Ref # 4

HERG Inhibition by Cisapride

Ref # 6

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.

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)

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

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 ,Tmax,, t1/2

QT-Interval is corrected for heart rate (QTc) Plot QTc versus [drug] in plasma Crossover design is often better than

parallel

Estimation of CV Safety Margins

Ref # 7

Canine Purkinje Fiber Assay

Ref # 8

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

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- www.torsades.org

References1) 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.

References6) 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.

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)

http://www.fda.gov/cder/guidance/index.htm