Stephanie van Hoppe

67 Brain accumulation of osimertinib and its active metabolite is restricted by ABCB1 & ABCG2 Supplemental Figure 3 - Tissue concentration ( A, C, E & G ) and tissue accumulation ( B, D, F & H ) of osimertinib at 24 h in maleWT, Abcb1a/1b;Abcg2 -/- , and Cyp3a -/- mice following a single oral dose of 10 mg/kg osimertinib. Statistical differences were assessed using one-way analysis of variance (ANOVA) followed by Tukey’s post-hoc multiple comparisons. Statistically significant differences were: *, P < 0.05; **, P < 0.01; ***, P < 0.001 compared with WT mice. Tissue accumulation of osimertinib was calculated by determining the osimertinib tissue concentration relative to its plasma AUC 0-24h . Note that at 24 h, brain concentrations of osimertinib inWT mice were below the limit of quantification (1 ng/ml). These values resulted occasionally in negative figures and were hence assumed to be zero for calculations. Values are shown as mean ± SD. N = 5 mice per group. Supplemental Figure 4 - Plasma-time curve of AZ5104 ( A ) and AZ5104 to osimertinib concentration ratio ( B ) in male wild-type (WT) (black circles), Abcb1a/1b -/- (dark blue squares), Abcg2 -/- (green triangles) and Abcb1a/1b;Abcg2 -/- (sky-blue triangles) mice, over 90 minutes after oral administration of 10 mg/kg osimertinib. Data are given as mean ± SD. N = 5-6 mice per group. Supplemental Figure 4. Plasma-time curve of AZ5104 ( A ) and AZ5104 to osimertinib concentration ratio ( B ) in male wild-type (WT) (black circles), Abcb1a/1b -/- (dark blue squares), Abcg2 -/- (gree triangles) and Abcb1a/1b;Abcg2 -/- (sky-blue triangles) mice, over 90 minutes after oral administration of 10 mg/kg osimertinib. Data are given as mean ± SD. N = 5-6 mice per group. 0.0 0.5 1.0 1.5 0 10 20 30 40 50 time (h) AZ5104 plasma concentration (ng/ml) WT Abcb1a/1b-/- Abcg2 -/- Abcb1a/1b;Abcg2-/- 0.0 0.5 1.0 1.5 0.0 0.1 0.2 0.3 0.4 time (h) AZ5104 to osimertinib ratio WT Abcb1a/1b-/- Abcg2 -/- Abcb1a/1b; Abcg2-/- A B