Fig. 6. Simulated versus observed plasma concentration-time profiles of dasatinib and pravastatin in healthy volunteers following oral administration.

(A) Dasatinib 100 mg single dose and (B) dasatinib 50 mg twice daily. The grey thin lines represent simulated individual trials (50) of 10 subjects using a population of 500 virtual subjects (10% female, 23–59 years) and 50 trials of 21 male subjects using a population of 1050 virtual subjects (19–47 years) for figure A and B, respectively. The black thin lines represent the upper (95^th) and lower (5^th) percentiles and the thick black line represents the simulated mean of the healthy volunteers population (n=500 for A and n=1050 for B). The circles denote mean values from the clinical study by Yago et al., 2014³⁵ and Eley et al., 2009⁵⁰ for figure A and B, respectively. (C) Simulated versus observed plasma concentrations of pravastatin following co-administration of a single dose pravastatin (40 mg) with placebo (black line), rifampicin (600 mg) (black dashed line) or dasatinib (100 mg) (grey dashed line). Lines represent the mean of simulated virtual populations of 400 healthy volunteers (50% female, 20–50 years). Note that the pravastatin placebo simulation and the pravastatin-dasatinib simulation have a significant overlap. (D) Predicted AUCR for the interaction of dasatinib on pravastatin based on a sensitivity analysis of estimated OATP inhibition data. Key from right to left: open triangle (Δ) – K_i values based on experimental IC₅₀ determined without pre-incubation, closed square (■)– K_i values based on experimental IC₅₀ determined with pre-incubation, open square (□) – K_i values based on experimental IC₅₀ determined with pre-incubation as IC₅₀/2, closed circle (●) – K_i values based on experimental IC₅₀ determined with pre-incubation and calibrated using CsA.