PI-105

S. Polak; Simcyp, Sheffield, United Kingdom

BACKGROUND: The aim of the study was to assess whether modeling and simulation can be used to predict cardiac consequences of an example drug with use of middle-out approach by utilization early clinical (PK) and in vitro measured, drug triggered cardiac ionic currents disruption data, and therefore support activities leading towards limiting TQT studies and increasing role of phase I clinical trial results and in vitro data connected by mathematical models.
METHODS: Flecainide was chosen as a model drug (diverse in nature cardiac effects). Simcyp (V13.1) was used to simulate individual plasma concentrations based on the pre-clinical and clinical (CLpo) ADME data. Exposure was further utilized as CSS (V1.0) input together with in vitro channels inhibition data (IC50 values in µM): IKr=3.91, INa=0.9. Simulations were set to mimic clinical trial: n=12 (7 EM and 5 PM for 2D6), mean age 25.8±4.5 years, 50 and 100 mg tablets, multiple dosing (BID - 9am/9pm) with plasma concentration and effect measured after final dose (5th day). PD endpoints included change of ECG parameters (QRS, QT/QTcF, JT/JTcF).
RESULTS: Table 1 presents a comparison of clinically observed and simulated PD data (all differences statistically insignificant).
CONCLUSION: The results support predictive abilities of the in silico simulations for the cardiac safety assessment.

Observed vs. predicted clinical endpoints.

EM 50mg EM 100mg PM 50mg PM 100mg
average SD average SD average SD average SD
OBSERVED ΔQRS [%] 0.3 3.7 8.9 2.8 -1.0 4.9 7.7 3.3
ΔQTc [%] 1.7 1.6 6.8 6.2 1.2 3.2 5.5 4.4
ΔJTc [%] 2.1 2.0 6.3 7.7 1.9 3.3 4.9 5.0
PREDICTED ΔQRS [%] 3.3 5.3 5.7 3.1 3.4 2.2 6.7 1.8
ΔQTc [%] 3.5 5.3 5.5 4.8 3.0 5.2 3.6 6.9
ΔJTc [%] 3.6 6.4 5.5 5.7 3.0 6.2 3.0 8.2