Table 3.
Drug-Induced Abnormalities Observed in In Silico versus In Vitro Nonpaced hiPSC-CMs
| Drug | Dose | In Silico |
In Vitro |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| OK | Q | RA | IRR | RESAC | OK | Q | RA | IRR | RESAC | Tachy | ||
| Astemizole | D1 | 476 | 1 | – | – | – | 6 | – | – | – | – | – |
| D2 | 475 | 2 | – | – | – | 6 | – | – | – | – | – | |
| D3 | 466 | 2 | 4 | 5 | – | 6 | – | – | – | – | – | |
| D4 | 432 | 2 | 38 | 5 | – | 6 | – | – | – | – | – | |
| Bepridil | D1 | 472 | 5 | – | – | – | 5 | – | – | 1 | – | – |
| D2 | 466 | 11 | – | – | – | 6 | – | – | – | – | – | |
| D3 | 365 | 107 | 3 | 2 | – | 6 | – | – | – | – | – | |
| D4 | 27 | 444 | 6 | – | – | – | 6 | – | – | – | – | |
| Diltiazem | D1 | 477 | – | – | – | – | 5 | – | – | 1 | – | – |
| D2 | 452 | 25 | – | – | – | 4 | – | 1 | 1 | – | – | |
| D3 | 204 | 269 | – | 4 | – | 6 | – | – | – | – | – | |
| D4 | 12 | 444 | 1 | – | 20 | – | – | – | 1a | – | 6a | |
| Dofetilide | D1 | 474 | 2 | – | 1 | – | 4 | – | – | 2 | – | – |
| D2 | 470 | 2 | – | 5 | – | 5 | – | – | 1 | – | – | |
| D3 | 466 | 2 | 3 | 6 | – | 5 | – | – | 1 | – | – | |
| D4 | 461 | 3 | 4 | 9 | – | – | – | 6a | – | – | 2a | |
| D5 | 455 | 3 | 12 | 7 | – | |||||||
| D6 | 435 | 1 | 39 | 2 | – | |||||||
| D7 | 414 | 1 | 59 | 3 | – | |||||||
| Ibutilide | D1 | 477 | – | – | – | – | 5 | – | – | 1 | – | – |
| D2 | 477 | – | – | – | – | 3 | – | – | 3 | – | – | |
| D3 | 474 | 2 | – | 1 | – | – | – | 6 | – | – | – | |
| D4 | 427 | 1 | 47 | 2 | – | – | – | 5 | – | – | 1 | |
IRR, irregular rhythm; OK, spontaneous beating with no abnormalities; Q, quiescence; RA, repolarization abnormality (EADs and/or repolarization failure); RESAC, residual activity; Tachy, tachyarrhythmic oscillations; –, phenotype not observed.
a
In vitro observations showed more than one abnormal phenotype. For dofetilide, D5 = 10× EFTPCmax, D6 = 30× EFTPCmax, and D7 = 100× EFTPCmax were tested only in silico to assess whether doses higher than D4 could trigger more abnormalities.