HESI/ILSI Health and Environmental Sciences Institute

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HESI/ILSI Health and Environmental Sciences
Institute
Workshop session I Molecular and Cellular
Biology Underlying TdP
Co-Chairs Craig January and Dan
Roden Rapportuers Kristy Bruse and Ying Ying
Zhou Workshop participants Blake Anson, Siham
Biade, Eve Bijaoui, Albert Defelice, Michael
Nabauer, Guy Salama, Peter Siegle, Steve Sorota,
Antoniao Zaza, Ravikumar Peri, Karin Sipido
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Goal 1 Define the relationship between IKr block
and risk for drug-induced QT prolongation and TdP

• What is the relationship between hERG QT
  prolongation TdP?
• Genetic influences
• Cellular changes
• Single channel event
• APD event
• Other mechanisms
• Clinical event
• Are there other ways to predict risk for TdP?

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Goal 1. The relationship between drug-induced IKr
block and risk for drug-induced QT
prolongation/TdP

• IKr blockade

other currents mechanisms
Increased APD/EADS
cell Ca2, ?
Increased QT interval
electrical heterogeneity, ?
TdP event
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Goal 1. Problem Quantifying drug-induced IKr
block

• Potency
• Relative potency compared to target pharmacophore
• Need to compare to positive control (compare IC50
  or percent channel blockade)
• Kinetics/voltage dependence
• Testing system
• Protocol-dependent, cell type, solutions,
  temperature, intrinsic drug properties,
  adsorption to tubing/set-up, etc
• Subunit interactions
• Transfected cell line properties
• Protein binding

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Goal 1. Future needs Quantifying drug-induced
IKr block

• To standardize potency/effect
• Standardize test systems where possible
• Standardize the verbiage

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Goal 1. IKr blockade affects on action potential

• IKr blockade ? ?other mechanisms? ??? action
  potential effects
• Discordance What is an EAD?
• There is not agreement as to the
  electrophysiological shape of an EAD.
• Agreement irrespective of the shape definition,
  EADs can enhance dispersion of repolarization
  and/or cause triggered activity ?TdP

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Goal 1. IKr blockade affects on action potential

• Unknown what are these other mechanisms?
• Altered channel trafficking as an alternate
  mechanism to reduce IKr, then how often? how
  important?
• Other inward/outward current data may be useful
  for predictivity
• Could in silico assist in assimilation of other
  ion current data results
• AP interpretation from In vitro data- need a
  positive control reference and understanding of
  the strengths/weaknesses of the assay(s)
• Future should we evaluate other ion channels to
  better predict risk for TdP? Do not
  over-interpret the IKr data
• Note, other targets may be protective against
  the IKr blockade

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Goal 1. Delayed repolarization (?APD/EADs)
influences on QT prolongation/TdP

• Unknowns
• How do ?APD/EADs perturb QT duration or
  morphology alterations (e.g. TdP) ?
• Rate dynamicity- is this important? Does it
  matter how you change the rate?
• Is there an optimal heart rate correction factor
  for QT interval (e.g. QTc)? Is the beat to beat
  variance of QT a more relevant evaluation?
• How are U-waves interpreted?
• What is QT prolongation?

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Goal 1. Relationship between QT prolongation and
TdP

• Unknowns
• In face of QT prolongation, what predicts TdP?
  What terminates TdP?
• What percentage of patients with QT prolongation
  are at risk of TdP?
• What percentage of patients with QT prolongation
  are resistant to TdP?
• Concerns
• How is TdP defined clinically? Is there a
  distinct difference from polymorphic ventricular
  tachycardia and TdP (associated with long QT)?
• How is TdP identified in the clinic? How many
  cases are not identified and end up as syncope,
  sudden death or possibly resolve?

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Goal 2. Evolving tools to move to better
predictors of drug-induced TdP

• In silico modeling in drug safety/mechanisms
• In vitro cell biology of IKr
• Stem cell research and more
• Genetic screening/other biomarkers

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Goal 2. in silico modeling in drug
safety/mechanisms

• In silico- hypothesis generators
• Pharmacophore (QSAR) modeling-rank ordering tool
  for early development
• Purpose- to refine chemical structure design for
  future in vitro testing
• Modeling for AP/whole heart
• Advantages test hypotheses not otherwise
  accessible
• Limitations never proves anything. Limited to
  current knowledge.
• Structural modeling of hERG and other ion channels

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Goal 2. In vitro cell biology of IKr

• Future further understand the regulation and
  dynamics of the IKr channel.
• Lipid/structural influences, subunits,
  interacting proteins, transcriptional/post-transcr
  iptional regulation, and post-translational
  processing.

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Goal 2. Consequences of modifying IKr

• Altered intracellular calcium dynamics
• Activation of CaM Kinase II ?
• Adrenergic changes/autonomic tone
• Transcription, translation, etc.
• Intracellular magnesium and potassium
  concentrations

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Goal 2. Cutting Edge Science! Stem cell
research and more

• 5 year deliverable
• Direct high throughput screening for drug effects
  on action potential, Ca2i, arrythmogenicity of
  mammalian and human myocytes
• This may also include transgenic non-rodent
  animal models

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Goal 2. Need for Genetic screening/biomarkers

• Discovering and characterizing of sequence
  variants in patient populations. Role of known
  variants
• For drug screening? (Not yet)
• For screening patients for TdP susceptibility
• Global effort- academia, industry, regulatory
  agencies Concerted effort to ascertain
  information (e.g. DNA, serum, ECG samples) from a
  large number patients with drug-induced TdP.
  Platform for discovery.