Fig. 4: Retrospective safety assessment of AZD1979.
a Distribution of AEGIS DILI scores after treatment of PHH spheroids from three donors with AZD1979 at concentrations ranging between 0.01 and 10-times Cmax. The red area marks a high-risk zone with 90% confidence that a treatment is at high risk for DILI, see Fig. 1c. b Observed and simulated (see Methods for details) change in ATP in galactose media (n = 3) and basal oxygen consumption rate (OCR) from the Seahorse assay (n = 5 for all doses, except n = 2 for 50 µM and n = 4 for 1.5625 µM) from HepG2 cells dosed with AZD1979 relative DMSO. Data presented as mean ± standard deviation. c PBPK simulation of plasma and liver concentrations of AZD1979 overlaid with clinical plasma levels of AZD1979 from patients receiving 300 mg AZD1979. Clinical plasma levels are visualised as the geometric mean ± geometric mean standard deviation (n = 6). d Dynamic DILIsym® simulation of ALT (normalised to ULN) showing the 5th percentile, median and 95th percentile of 285 individuals from a virtual population incorporating physiological variability of liver function, including ALT turnover and mitochondrial function. Clinical ALT values for six patients receiving 300 mg AZD1979 are shown as circles. Black and red dashed line show 1*ULN and 3*ULN, respectively.
