Figure 4. Validation of the drugs computational screening pipeline prototype with human clinical data.

(A) Heart rate corrected pseudo ECG ( ΔQT_C interval) was computed from a 1-dimensional strand of O’Hara-Rudy human cardiac ventricular myocytes for pacing frequencies between 43 – 75 bpm for a range of dofetilide concentrations (blue) compared to clinical data (red). (B) Comparison of human clinical data showing control and dofetilide affected rate corrected QT intervals^{10, 56} (black and red lines) and simulated mean values under the same conditions (blue asterisks). Red line: two subjects received a single dose of 0.5 mg (population’s mean maximum concentration C_max is 2.7±0.3 ng/mL). Blue asterisks (*): concentration 2.72 ng/mL (~6.16 nM) was used in the simulations. Black lines: subjects received 0.5 to 0.75 mg twice a day. (C) The clinically observed and in silico prediction of QT intervals over a wide range of preceding RR intervals after 2.72 ng/mL dofetilide application. Rate dependent changes in the QT interval were tracked as the slope of the linear regression line estimating the QT – $\sqrt{RR}$ relation. (D) Model predicted ΔQT_C intervals with 2.5 mg/L moxifloxacin application (blue asterisks). Color symbols with error bars: clinical data after 400 mg moxifloxacin oral dose (maximum concentration C_max is between 2.3 to 3.7 mg/L).^59–65