Quantifying Risk of Delayed QT Prolongation of Ipatasertib in Preclinical and Clinical Studies in Cancer Patients

Figures

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  FIGURE 1. Flow chart outlining clinical QTcF and drug sampling by study and dosing. SD, Single Dose; SS, Steady State.

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  FIGURE 2. (A) QTcF measurements for patients in the GP42658 Study. Blue lines represent QTcF measurements taken prior to the patient's first dose. Red lines represent post‐dose QTcF measurements at steady‐state (10 days of ipatasertib QD treatment). (B) ΔQTcF Measurements for patients in the GP42658 Study.

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  FIGURE 3. Percent inhibition of hERG potassium current after application of each concentration of ipatasertib (Mean ± SEM, black circles; n = 3). Data was fit to a dose–response binding equation (solid line) with IC50 = 23.7 μM and Hill coefficient = 1.

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  FIGURE 4. Hysteresis plots of mean ΔQTcF and mean ipatasertib concentrations after single dose by hours post dose and dose amount in the PAM4743g study. Lines connect points in ascending order of hours post dose.

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  FIGURE 5. Visualization of ΔQTcF and ipatasertib concentrations in the GP42658 study. (A) Ipatasertib concentrations post dose with solid line being a loess fit and the shaded area being the 95% CI of the loess fit. The individual gray lines are observed patient measurements. The lower left plot is of ΔQTcF post dose with solid line being a loess fit and the shaded area being the 95% CI of the loess fit. The individual gray lines are of patient individual ΔQTcF. (B) Hysteresis plot of mean ΔQTcF and mean ipatasertib concentrations are plotted by hours post dose. Lines connect points in ascending order (0, 1, 2, 3, 4, 6, 8, 12, 24 h post dose).