2. Why Cardiac Safety Testing?
S7B Guidance
Objective
− Identify potential of a test substance or its metabolites to delay ventricular
repolarization.
− Relate extent of delayed ventricular repolarization to concentrations of a test
substance and its metabolites.
Components that contribute to an assessment of cardiac risk
− In Vitro IKr Assay
– effect on native or expressed IKr (such as hERG)
− In Vivo QT Assay
– effect on QT interval
– this assay can be designed to meet the objective of both the ICH S7A (cardiovascular
core battery) and S7B
3. Ion Channels that Contribute to Cardiac Action Potential
voltage
K+ Channel Block
time
Ca2+ Channel Block
Na+ Channel Block
Normal AP
Inhibition of cardiac ion currents can alter QT interval, cause arrhythmia or death
Discovery Safety Testing: Detect cardiac safety liabilities early.
4. Cardiac Safety Testing Services
Radioligand Binding Assays (Pharmacology, Taiwan)
− Ideal for early hit selection profiling
Information Value
Cellular patch clamp assays (Pharmacology, Bothell)
− Automated Patch Clamp (APC) with PatchXpress
– cost-effective technology providing a medium-throughput method usually used in
discovery stage after hit selection
Tissue Assays (Pharmacology, Taiwan)
− L-Type Calcium channel Atrial Inotropy
In Vivo Assays – (Pharmacology, Taiwan and DSA, Lyon)
− - Cardiovascular, QTc Interval
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5. Ion Channel Testing Services
Services at Bothell Site
Non-GLP (10 day TAT)
- Cardiac
– hERG (Kv11.1)
– hNav1.5
– hCav1.2
- Immuno-suppression and Obesity
– hKv1.3
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6. Functional Ion Channel Services in Bothell
Discovery Safety Testing Fail Early
Crucial attributes for discovery assays:
Fast
10-day Turnaround time on Automated Patch Clamp (PatchXpress)
assays
Medium- to High-throughput capacity
Automated Patch Clamp (PatchXpress) assays are medium-throughput at
modest cost compared to conventional patch clamp
Predictive of clinical outcome
Over-expressed human cardiac ion channels that play central role in AP
hKv11.1 (hERG)
hNav1.5
hCav1.2
Assays validated against drugs with known cardiac liabilities or effects;
compare favorably with conventional patch clamp
