Stephanie van Hoppe

91 ABCB1 restricts brain penetration of the BTK inhibitor ibrutinib while CYP3A limits its oral bioavailability Supplemental Table 2 - Pharmacokinetic parameters of ibrutinib-DiOH at 8 h, 1 h and 20 minutes after oral administration of 10 mg/kg ibrutinib to female WT, Cyp3a -/- , Cyp3aXA, Cyp3aXV and Cyp3aXAV mice. Parameter Genotype Time WT Cyp3a -/- Cyp3aXA Cyp3aXV Cyp3aXAV AUC 0-8 (ng/ml.h) 8 h 3423 ± 213 229 ± 17 **** 965 ± 436 **** / # C max (ng/ml) 1779 ± 65.2 99.0 ± 44.3 497 ± 160 T max (minutes) 21 ± 8 30 ± 0 18 ± 7 AUC 0-1 (ng/ml.h) 1 h 992 ± 105 39.8 ± 7.0 **** C max (ng/ml) 1422 ± 295 51.8 ± 17.3 T max (minutes) 13 ± 3 38 ± 18 C liver (ng/g) 733 ± 178 68.7 ± 29.6 **** Liver to plasma ratio 1.23 ± 0.17 1.63 ± 0.24 Fold change 1 1.3 AUC 0-0.33 (ng/ml.h) 20 min 215 ± 81 17.3 ± 2.8 **** 76.4 ± 24.3 **** /#### 113 ± 44 **** /#### 136 ± 9 **** /#### C max (ng/ml) 1086 ± 316 88.8 ± 19.7 379 ± 119 488 ± 189 631 ± 50 T max (minutes) 14 ± 3 13 ± 3 11 ± 2 12 ± 3 9 ± 2 C liver (ng/g) 5287 ± 2522 244 ± 57 **** 651 ± 235 **** 674 ± 308 **** 729 ± 197 **** Liver to plasma ratio 4.38 ± 0.65 4.65 ± 0.56 3.05 ± 0.62 2.03 ± 1.48 *** 1.92 ± 0.60 *** Fold change 1 1.1 0.7 0.5 0.4 AUC, area under the plasma concentration-time curve; C max maximum DiOH concentration in plasma; T max , the time (h) after drug administration needed to reachmaximumplasma concentration; C brain , brain concentration; C liver , liver concentration. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001 compared to WT mice and #, P < 0.05; ##, P < 0.01; ###, P < 0.001 compared to Cyp3a -/- mice. Data are given as mean ± SD.