Stephanie van Hoppe

54 Chapter 3 Table 2 - Pharmacokinetic parameters of osimertinib over 1.5 h after oral administration of 10 mg/ kg osimertinib to male WT, Abcb1a/1b -/- , Abcg2 -/- , and Abcb1a/1b;Abcg2 -/- mice. Parameter Genotype  Wild-type Abcb1a/1b −/− Abcg2 −/− Abcb1a/1b;Abcg2 −/− Plasma AUC 0-1.5 (h*ng/ml) 227 ± 50 236 ± 77 225 ± 71 178 ± 78 fold change 1 1 1 0.8 C max (ng/ml) 236 ± 77 215 ± 108 279 ± 86 214 ± 114 T max (h) 1 1 1 1 C brain (ng/g) 2003 ± 1026 6929 ± 3161** 1350 ± 271 10135 ± 1942*** fold change 1 3.5 0.7 5.1 Brain to plasma ratio 14.5 ± 6.4 60.5 ± 36.7* 23.1 ± 3.7 93.0 ± 18.3*** fold change 1 4.1 1.6 6.4 P brain (h -1 ) 8.6 ± 3.6 32.8 ± 20.6 6.5 ± 2.3 64.3 ± 22.8*** fold change 1 3.8 0.8 7.5 C liver (ng/g) 3912 ± 1180 3934 ± 1842 3917 ± 362 2472 ± 494 fold change 1 1 1 0.6 Liver to plasma ratio 29.0 ± 9.2 33.4 ± 19.8 68.9 ± 16.8** 28.4 ± 14.2 fold change 1 1.2 2.4 1 P liver (h -1 ) 17.3 ± 4.6 17.6 ± 9.4 18.6 ± 5.5 15.7 ± 5.7 fold change 1 1 1 0.9 Brain to liver ratio 0.6 ± 0.3 2.1 ± 1.5 0.3 ± 0.1 3.6 ± 1.1*** fold change 1 3.5 0.5 6 AUC, area under the plasma concentration-time curve; C max , maximumdrug concentration in plasma;T max , time (h) to reach maximum drug concentration in plasma; C tissue , tissue concentration; P tissue , tissue accumulation. 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. Data are expressed as the mean ± SD. (n = 5-6). For some TKIs, such as brigatinib, we have previously observed that increased brain penetration of the drug due to the absence of Abcb1a/1b and Abcg2 activity at the BBB in mice was associated with acute lethal toxicity, whereas WT mice were completely unaffected by the same dose of brigatinib [45]. In contrast, in our current study for osimertinib we did not observe any indication for spontaneous toxicity in the Abcb1a/1b;Abcg2 -/- mice in either the 24-h or the 1.5-h experiments after a single 10 mg/kg oral dose.