Key result
The inter-facility variability of action potential parameters did not exceed intra-facility variability, and all 22 facilities successfully detected action potential duration prolongation by dl-sotalol.
A standardized action potential assay using isolated guinea-pig papillary muscles demonstrates low inter-facility variability, supporting its use as a reliable non-clinical evaluation system for QT prolongation.
Supports standardized non-clinical QT assays; leaves open human translation and regulatory adoption.
Sixteen pharmaceutical companies and 6 contract research organizations in QT PRODACT acquired data on the action potentials in isolated guinea-pig papillary muscles using a standard protocol established by the QT PRODACT. Inter- and intra-facility variability for each of the parameters in the pre-application values and Delta% change after vehicle (0.1% DMSO) or dl-sotalol (30 micromol/L) treatment were examined using a nested model. Inter-facility variability of each of the parameters in the pre-application values were Vmax>APDs=APD30-90>APA=RMP (descending order). The inter-facility variability of all of the parameters was almost the same or was less as compared with the intra-facility variability. Inter-facility variability for the Delta% change for each parameter after dl-sotalol treatment showed a tendency similar to the results for the pre-application values. Comparing the inter- and the intra-facility variability, the inter-facility variation did not exceed the intra-facility variation. All facilities found that dl-sotalol prolonged APD. Therefore, it is suggested that the test system using this standard protocol is useful as a non-clinical evaluation system for QT prolongation. Moreover, the results are considered to be directly comparable between multiple facilities.
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Yamazaki et al. (2005) studied QT prolongation (non-clinical assay validation) (n=132). dl-sotalol vs. vehicle (0.1% DMSO) was evaluated on Inter- and intra-facility variability of action potential duration (APD) and detection of APD prolongation. The inter-facility variability of action potential parameters did not exceed intra-facility variability, and all 22 facilities successfully detected action potential duration prolongation by dl-sotalol.
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