Stephanie van Hoppe

82 Chapter 4 Table 2 - Pharmacokinetic parameters of ibrutinib at 8 h, 1 h and 20 minutes after oral administration of 10 mg/kg ibrutinib to femaleWT, Cyp3a -/- , Cyp3aXA, Cyp3aXV and Cyp3aXAV mice. Parameter Genotype Time WT Cyp3a -/- Cyp3aXA Cyp3aXV Cyp3aXAV AUC 0-8 (ng/ml.h) 8 h 430.5 ± 96.59 4166 ± 317 **** 832 ± 521 #### C max (ng/ml) 609 ± 276 3865 ± 932 798 ± 404 T max (minutes) 7 ± 4 15 ± 8 9 ± 5 AUC 0-1 (ng/ml.h) 1 h 341 ± 59 1973 ± 670 **** C max (ng/ml) 748 ± 93 3305 ± 1425 T max (minutes) £ 5 13 ± 8 C brain (ng/g) 8.93 ± 4.58 111 ± 34.7 **** Brain to plasma ratio 0.081 ± 0.015 0.109 ± 0.021 Fold change 1 1.3 C liver (ng/g) 162.6 ± 76,4 1415 ± 409 **** Liver to plasma ratio 1.493 ± 0.095 1.384 ± 0.221 Fold change 1 0.9 Brain to liver ratio 0.054 ± 0.006 0.079 ± 0.010 Fold change 1 1.4 AUC 0-0.33 (ng/ml.h) 20 min 113 ± 67 988 ± 139 **** 423 ± 76 **** /#### 367 ± 57.53 **** /#### 194.5 ± 15.65 #### C max (ng/ml) 590.2 ± 261.0 4544 ± 505.6 2129 ± 360.8 1693 ± 280 1015 ± 73.4 T max (minutes) 13 ± 6 11 ± 3 7 ± 3 9 ± 4 £ 5 C brain (ng/g) 102 ± 60.5 468 ± 98.3 **** 133 ± 24.9 #### 89 ± 40.4 #### 38 ± 8.8 #### Brain to plasma ratio 0.256 ± 0.041 0.199 ± 0.027 * 0.190 ± 0.028 ** 0.117 ± 0.025 **** /### 0.112 ± 0.011 **** /### Fold change 1 0.7 0.7 0.5 0.4 C liver (ng/g) 2420 ± 1479 8178 ± 1380 **** 2147 ± 551.3 #### 2125 ± 701.3 #### 963.4 ± 207.2 #### Liver to plasma ratio 5.06 ± 0.96 2.78 ± 0.19 **** 2.36 ± 0.67 **** 1.70 ± 0.34 **** /# 1.66 ± 0.22 **** /# Fold change 1 0.5 0.5 0.3 0.3 Brain to liver ratio 0.043 ± 0.013 0.057 ± 0.005 0.063 ± 0.009 * 0.040 ± 0.010 # 0.039 ± 0.005 # Fold change 1 1.3 1.5 0.9 0.9 AUC, area under the plasma concentration-time curve; C max maximum ibrutinib concentration in plasma; T max , the time (h) after drug administration needed to reach maximum plasma 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; ####, P < 0.0001 compared to Cyp3a -/- mice. Data are given as mean ± SD