Table 1. Comparison of compound safety assays (hERG assay, APD assay in papillary muscle, Langendorff assay and on-chip MEA assay) for predictive clinical VT/TdP risk.
| Category | Drug | Clinical report | in vitro assay | On-chip MEA system | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| VT/VF/TdP | CMAX (μM) | hERG inhibition (%) | APD90 prolongation in papillary musole (ratio) | MAPD90 prolongation in Langendorff hearts (ratio) | Ref. dose (10 × CMAX) | FPD (ratio) | t-test | STVFPD (ratio) | t-test | Ref. dose (ca. 102 × CMAX) | Arrest (%) | Fib-like (%) | n | Score | ||
| I: Positive | Cisapride | (+) | 0.18 | 90.6 | 1.14 | 1.37E | 1 μM | 1.37 ± 0.07 | **** | 3.82 ± 0.85 | ** | 10 μM | 0 | 4 | 25 | High |
| DL-sotalol | (+) | 2.5 | 19.2 | 1.15 | 1.30 | 30 μM | 1.25 ± 00.05 | ** | 3.08 ± 0.86 | ns | 103 μM*7 | 5 | 0 | 38 | High | |
| E-4031 | (+) | 74.5 | 1.26 | 1.50E | 0.1 μM | 1.24 ± 0.08 | * | 2.67 ± 0.67 | * | 1 μM | 8 | 4 | 24 | High | ||
| Moxifloxacin | (+) | 10 | 51.4 | 1.44 | 1.87 | 300 μM | 1.60 ± 0.12 | *** | 5.61 ± 2.31 | ns | 102 μM | 0 | 0 | 27 | High | |
| II: False negative on APD in papillay muscle | Bepridil | (+) | 0.30 | 61.9*1 | 1.02 | 1.12 | 10 μM | 1.21 ± 0.12 | ns | 4.74 ± 2.26 | * | 10 μM | 5 | 5 | 20 | High |
| Astemizole | (+) | 0.002 | 105.4*2 | 1.01 | 1.27E | 1 μM | 1.08 ± 0.10 | ns | 3.54 ± 1.39 | * | 10-1 μM | 0 | 14 | 25 | High | |
| Paroxetin | (−/+) | 0.07 | (n.d.) | (n.d.) | (n.d.) | (n.d.) | 1.30 ± 0.06 | **** | 2.27 ± 0.41 | * | 10 μM*7 | 13 | 0 | 24 | High | |
| Thioridazine | (+) | 1.8 | 87.8*3 | 1.01 | 1.16 | 10 μM | 1.17 ± 0.03 | ** | 1.90 ± 0.30 | * | 10 μM | 0 | 0 | 22 | High | |
| Flecainide | (+) | 0.43 | 88.3*4 | 0.75 | 1.29*6 | 30 μM | 1.00 ± 0.05 | ns | 3.01 ± 0.65 | *** | 102 μM*7 | 13 | 0 | 24 | High | |
| Citalopram | (+) | 0.27 | 83.5 | 0.95 | (n.d.) | 10 μM | 0.86 ± 0.04 | **** | 2.75 ± 0.78 | * | 10 μM | 12 | 0 | 25 | High | |
| Terfenadine | (+) | 0.22 | 94.2*5 | 0.98 | 1.05 | 10 μM | 0.98 ± 0.04 | ns | 2.05 ± 0.53 | ns | 10 μM | 21 | 3 | 34 | High | |
| III: False positive on hERG | Diltiazem | (−) | 0.11 | (+) | (−) | (n.d.) | 10 μM | 0.93 ± 0.08 | * | 1.70 ± 0.43 | ns | 1 μM*8 | 50 | 0 | 12 | Low |
| Ebastine | (−) | 0.16 | (+) | (−) | (−) | 0.3 μM | 1.07 ± 0.03 | ns | 1.64 ± 0.28 | ns | 1 μM | 0 | 0 | 18 | Low | |
| Verapamil | (−) | 0.17 | 99.2 | 0.95 | 0.79 | 10 μM | 0.51 ± 0.05 | **** | 0.97 ± 0.18 | ns | 10 μM | 49 | 0 | 43 | Low | |
| IV: Negative | Famotidine | (−) | 0.19 | (−) | (−) | (−) | 10 μM | 1.02 ± 0.02 | ns | 1.03 ± 0.09 | ns | 10 μM | 0 | 0 | 32 | Low |
| Levofloxacin | (−) | 22 | 13.2 | 1.07 | 1.18 | 300 μM | 0.80 ± 0.14 | ** | 1.27 ± 0.25 | ns | 103 μM | 40 | 4 | 25 | Low | |
| DMSO | (−) | (n.d.) | (n.d.) | (n.d.) | (n.d.) | 1.06 ± 0.02 | - | 1.38 ± 0.24 | - | 0.1% | 6 | 0 | 31 | No | ||
| PBS | (−) | (n.d.) | (n.d.) | (n.d.) | (n.d.) | 1.05 ± 0.02 | - | 1.23 ± 0.11 | - | - | 0 | 0 | 25 | No | ||
Data on hERG inhibition, APD prolongation in papillary muscle and in Langendorff hearts, and on-chip MEA assay was based on our results (Figs. 2). + and – show the positive and negative risk on the results of our assays. Short show the APD/FPD shortening on the results of our assays. (+) or (−) in present the positive or negative risk based on the references and pharmaceutical attachments. The data (the relative ratio against the control) is shown as only mean for on hERG inhibition, APD prolongation in papillary muscle and in Langendorff hearts and as mean ± S.E. for on-chip MEA assay. The reference concentrations (Ref. dose) show the concentration referred the experiments (hERG assay, APD assay in papillary muscle, Langendorff assay). VT/TdP risk is compiled from the literature.
Eindicates EAD appearances on the Langendorff assays.
*1: 0.3 μM bepridil;
*2: 0.1 μM astemizole;
*3: 3 μM thioridazine;
*4, *6: 10 μM flecainide;
*5: 1 μM terfenadine.
Abbreviations: phosphate-buffered saline (PBS), and dimethyl sulfoxide (DMSO). Red hatched area indicates positive (+risk), and blue area indicates negative (-risk) judgment using each method.