Test compound selection– Process, methodology, and selected compounds for CIPA efforts David E. Gutstein, MD, for the CSRC Compound Selection Team for CIPA CSRC/HESI/SPS/FDA Meeting December 11, 2014
▷ Provide a battery of compounds for training, testing and validating the in silico and stem cell CIPA models 。Build/calibrate model using compounds with well- characterized torsadogenic risk 。Test/validate model using subset of compounds in the current set › Compounds considered as test cases › Intent of compound set was to provide varied spectrum of multiple electrophysiologic parameters: 。Degree of torsadogenic clinical risk 。Actions on ion channels, with attention to multi-channel blockers; Varying levels of block at clinical exposures Inclusion of some compounds with non-hERG TdP risk
› Selected compounds should not have major proarrhythmic active metabolites › No insoluble compounds › Well defined cardiac electrophysiology › Ranking compounds with regard to clinically demonstrated torsadogenic risk/occurance based partly on published reports, FDA AERS database, other data sources and expert opinion › Compounds grouped into ‘high’, ‘intermediate’ and ‘very low’ (i.e., none) risk categories 。Intermediate risk compounds grouped due to difficulty parsing out risk levels within the intermediate bucket 。 ‘Very low’ risk actually indicates no discernable risk Culled from much larger list of compounds
トRedfern, et al, 2003: Category 1: Class Ia and Class III anti-arrhythmics, block I κ , and prolong QT o Category 2: agents withdrawn due to risk of TdP Category 3: measurable incidence or numerous case reports of TdP in humans Category 4: isolated reports of TdP in humans Category 5: no published reports of TdP in humans when used alone Mirams, et al, 2011: Updated assignments to Redfern categories Kramer, et al, 2013: torsadogenic (+TdP) or non-torsadogenic (-TdP) Credible Meds: categories include Risk of TdP, Possible Risk of TdP Pulozzi, et al, 2009: ROR + 95% CI calculated for each drug FDA AERS Database: Indicator of risk = EB05トトトトト. FDA labeling o Black box warnings 。 Warnings and precautions Compound-specific referencesトMultiple classification schemes, with differing numbers of categoriesトKey for our purpose was to identify gradation of riskト5
▷ Initial list of 28 compounds provided for testing and validation of in silico and stem cell CIPA models › Compounds categorized into 3 risk groups according to published/publically available data and expert clinical opinion
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› Why did we end up with 3 risk categories? 。 Uncertainties • Exposure: critical determinant of potential torsadogenicity • Patient status and its influence of arrhythmogenic substrate—e.g., ICU patient vs healthy outpatient • Risks conferred by concomitant medications •  Lack of objective data, denominator for reports of TdP •  Limited categories for some classification systems (e.g., Credible Meds, Kramer et al) ▷ What was the thinking behind specific classification assignments? 。Risperidone: low vs intermediate vs high risk? 。 Quinidine: hERG blockade at concentrations lower than INa blockade; relevant concentrations will need to be used for model testing thow certain are we about classifications?
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