Stephanie van Hoppe

55 Brain accumulation of osimertinib and its active metabolite is restricted by ABCB1 & ABCG2 L imi t ed impa c t o f mou s e Cy p3a and human C YP3A4 on o s ime r t i n i b pha rma c o k i ne t i c s i n mi c e Although the 24 h experiment did not suggest a clear impact of mouse Cyp3a on osimertinib plasma pharmacokinetics, we did assess a possible impact of Cyp3a deficiency, and/or the transgenic overexpression of human CYP3A4 in liver and intestine, on the plasma kinetics and tissue distribution of osimertinib 1.5 h after oral administration at 10 mg/kg to male mice. Figure 4 and Supplemental Table 1 show that, unexpectedly, and in spite of the high interindividual variation, the plasma AUC 0-1.5h was significantly lower in both the Cyp3a -/- and CYP3A4-transgenicmice compared to theWT strain. For the Cyp3a -/- mice this contrasts with the 24 h plasma data, and it may be that the high interindividual variation played a role in this result. A possible lowering of the plasma AUC in Cyp3a -/- mice might in theory be caused by compensatory upregulation of other osimertinib-clearing proteins. A possible slight (but significant, P < 0.05) further decrease in the plasma AUC 0-1.5h in the CYP3A4-transgenic mice compared to the Cyp3a -/- mice (Supplemental Table 1) might suggest a comparatively small impact of the human CYP3A4 expression in clearing osimertinib. However, all these effects are very modest. Also, when considering the various tissue concentrations of osimertinib, values Figure 3. Brain and liver concentration ( A, D ), tissue-to-plasma ratio ( B, E ) and relative tissue accumulation ( C, F ) of osimertinib in male WT, Abcb1a/1b -/- , Abcg2 -/- , and Abcb1a/1b;Abcg2 -/- mice 1.5 h after oral administration of 10 mg/kg osimertinib. *, P < 0.05; **, P < 0.01; ***, P < 0.001 compared to WT mice. Data are presented as the mean ± SD. N = 5 mice per group. WT Abcb1a/1b-/- Abcg2-/- Abcb1a/1b;Abcg2-/- 0 5000 10000 15000 Brain concentration (ng/g) *** *** *** *** WT Abcb1a/1b-/- Abcg2-/- Abcb1a/1b;Abcg2-/- 0 2000 4000 6000 8000 Liver concentration (ng/g) WT Abcb1a/1b-/- Abcg2-/- Abcb1a/1b;Abcg2-/- 0 50 100 150 Brain to plasma ratio *** *** ** WT Abcb1a/1b-/- Abcg2-/- Abcb1a/1b;Abcg2-/- 0 20 40 60 80 100 Liver to plasma ratio WT Abcb1a/1b-/- Abcg2-/- Abcb1a/1b;Abcg2-/- 0 20 40 60 80 100 Brain accumulation (h -1 ) *** ** *** WT Abcb1a/1b-/- Abcg2-/- Abcb1a/1b;Abcg2-/- 0 10 20 30 Liver accumulation (h -1 ) 1.5 h experiment A B C D E F Figure 3. Brain and liver concentration ( A, D ), tissue-to-plasma ratio ( B, E ) and relative tissue accumulation ( C, F ) of osimertinib in male WT, Abcb1a/1b -/- , Abcg2 -/- , and Abcb1a/1b;Abcg2 -/- mice 1.5 h after oral administration of 10 mg/kg osimertinib. *, P < 0.05; **, P < 0.01; ***, P < 0.001 compared to WT mice. Data are presented as the mean ± SD. N = 5 mice per group.