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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. Background.
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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
Background • A number of non-cardiovascular drugs withdrawn from the US market due to reports of sudden cardiac death, arrhythmias and QT-interval prolongation: • Terfenadine (Seldane) - 21 deaths in UK (51% cardiac related) – withdrawn in 1997 after approval of Fexofenadine • Sertindole – 27 deaths in US (59% cardiac related)- 1.3% of clinical trial patients – voluntary withdrawal in 1998 •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
What is Torsade de Points (TdP)? Ref # 2 Note: Intravenous dose of Haloperidol, ICU patient, ~170 mg in 24 hours
What Kind of Drugs Can Induce QT-Interval Prolongation? Comprehensive list www.torsades.org 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
References • Brown, A.M. and Rampe, D. (2000). Drug-Induced QT Syndrome: Is HERG the Root of All Evil. Pharmaceutical News 7, 15-20. • 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. • Yap, Y.G. and Camm, A.J. (2003). Drug induced QT prolongation and torsade de pointes. Heart 89: 1363-1372. • 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. • Wysowski, DK. and Bacsanyi, J. (1996). Cisapride and Fatal Arrhythmia. N Engl. J. Med. 335 (4), 290-291.
References • 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 • 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. • 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