Stephanie van Hoppe

77 ABCB1 restricts brain penetration of the BTK inhibitor ibrutinib while CYP3A limits its oral bioavailability Possibly related to this change-over, we observed that under these circumstances the plasma AUC of ibrutinib in Abcb1a/1b;Abcg2 -/- as well as Abcb1a/1b -/- mice was almost 2-fold lower than that in WT mice, whereas Abcg2 -/- mice behaved more or less like WT mice (Figure 2A, Table 1). In other respects, however, the plasma pharmacokinetics in WT mice of both ibrutinib and ibrutinib-DiOHwere very similar to those seen in the pilot experiment, with rapid absorption of ibrutinib (T max before 5 min), a T max of ibrutinib- DiOH around 15 min (Figure 2B, Supplemental Table 1), and a ibrutinib-DiOH/ibrutinib ratio rising above a factor of 5 well within 1 hr (Supplemental Figure 4). The AUC 0-1 h for ibrutinib in WT mice was also very similar for both experiments (274 and 340 h.ng/ ml, respectively). Although there was a tendency for the ibrutinib-DiOH/ibrutinib ratio to be higher in the Abcb1a/1b;Abcg2 -/- as well as the Abcb1a/1b -/- mice compared to the WT mice, this did not reach statistical significance (Supplemental Figure 4). Abcg2 -/- mice behaved generally similar to WT mice in this respect. Thus, apart from the impact of Abcb1 deficiency, which resulted in ~2-fold lower plasma levels of ibrutinib in the second, but not the first, experiment, there does not seem to be a major impact of Abcb1 and/or Abcg2 on ibrutinib to ibrutinib-DiOH conversion. Table 1 - Pharmacokinetic parameters of ibrutinib at 8 and 1 h after oral administration of 10 mg/kg ibrutinib to female WT, Abcb1a/1b -/- , Abcg2 -/- and Abcb1a/1b;Abcg2 -/- mice. Parameter Genotype Time WT Abcb1a/1b -/- Abcg2 -/- Abcb1a/1b;Abcg2 -/- AUC 0-8 (ng/ml.h) 8 h 431 ± 97 404 ± 78 C max (ng/ml) 609 ± 276 837 ± 131 T max (minutes) 7 ± 4 5 ± 0 AUC 0-1 (ng/ml.h) 1 h 340 ± 59 190 ± 69 *** 350 ± 34 ### 169 ± 31 *** C max (ng/ml) 748 ± 93 455 ± 164 751 ± 95 372 ± 107 T max (minutes) £ 5 £ 5 7 ± 3 6 ± 2 C brain (ng/g) 8.93 ± 4.58 18.3 ± 9.86 9.41 ± 1.86 ## 25.9 ± 10.4 ** Brain to plasma ratio 0.081 ± 0.015 0.366 ± 0.086 *** 0.084 ± 0.007 #### 0.481 ± 0.074 **** Fold change 1 4.5 1 5.9 C liver (ng/g) 162 ± 76 54.3 ± 23 152 ± 37 77 ± 24 Liver:plasma ratio 1.49 ± 0.10 1.39 ± 0.25 1.36 ± 0.19 1.50 ± 0.21 Fold change 1 0.9 0.9 1 Brain to liver ratio 0.05 ± 0.01 0.31 ± 0.05 **** / # 0.06 ± 0.01 #### 0.33 ± 0.08 **** Fold change 1 5.7 1.2 6.1 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; P brain , brain accumulation (C brain divided by AUC); C liver , liver concentration; P liver , liver accumulation (C liver divided by AUC). *, 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 Abcb1a/1b;Abcg2 (-/-) mice. Data are given as mean ± SD.