Stephanie van Hoppe

52 Chapter 3 Table 1 - Pharmacokinetic parameters of osimertinib over 24 h after oral administration of 10 mg/ kg osimertinib to male WT, Abcb1a/1b;Abcg2 −/− and Cyp3a −/− mice. Parameter Genotype Wild-type Abcb1a/1b;Abcg2 −/− Cyp3a −/− Plasma AUC 0-24 (h*ng/ml) 1833 ± 343 2639 ± 842 1418 ± 290 fold change 1.0 1.4 0.8 C max (ng/ml) 272 ± 21 418 ± 167 341 ± 74 T max (h) 1 1 1 C brain (ng/g) < 1 183 ± 145*** 1.8 ± 1.0* /### P brain (*10 -3 h -1 ) < 1 70.8 ± 59.8*** 1.4 ± 0.9* /### C liver (ng/g) 9.1 ± 8.4 223 ± 48*** 21.6 ± 39.8 ### fold change 1 24.4 2.4 P liver (*10 -3 h -1 ) 4.9 ± 5.1 87.0 ± 28.1*** 3.0 ± 1.4 ### fold change 1 17.7 0.6 AUC, area under the plasma concentration-time curve; C max , maximum drug concentration in plasma; T max , time (h) to reach maximum drug concentration in plasma; C tissue , tissue concentration; P tissue , tissue accumulation. The lower limit of quantification (LLoQ) value for osimertinib was set at 1 ng/ml. Osimertinib plasma concentrations in all the groups and brain concentrations in WT mice at 24 h were below the LLoQ. These values resulted occasionally in negative figures and were hence assumed to be zero for calculations. For statistical comparison the C brain and P brain values for WT mice (< 1) were assumed to be 1.0 ± 1.0. Statistical differences were assessed using one-way analysis of variance (ANOVA) followed by Tukey’s post-hoc multiple comparisons. *, P < 0.05; **, P < 0.01; ***, P < 0.001 compared to WT mice. # , P < 0.05; ### , P < 0.001 compared to Abcb1a/1b;Abcg2 −/− mice. Data are expressed as the mean ± SD. (n = 5-6). Figure 2 - Plasma concentration-time curves of osimertinib in male wild-type (WT) (black circles), Abcb1a/1b -/- (dark blue triangles), Abcg2 -/- (green diamonds) and Abcb1a/1b;Abcg2 -/- (light-blue squares) mice, over 90 minutes after oral administration of 10 mg/kg osimertinib. Data are given as mean ± SD. N = 5-6 mice per group. Figure 2. Plasma concentration-time curves of osimertinib in male wild-type (WT) (black circles), Abcb1a/1b -/- (dark blue triangles), Abcg2 -/- (gr en diamonds) an Abcb1a/1b;A cg2 -/- (light-blue squares) mice, over 90 minutes after oral administration of 10 mg/kg osimertinib. Data are giv n as mean ± SD. N = 5-6 mice per group. 0 10 20 30 40 50 60 70 80 90 0 100 200 300 400 time (minutes) Osimertinib plasma concentration (ng/ml) WT Abcb1a/1b-/- Abcg2/Abcb1a/1b-/- Abcg2-/-