Stephanie van Hoppe

107 Brain accumulation of ponatinib and its active metabolite is limited by ABCB1 and ABCG2 Ava i l ab i l i t y o f o r a l pona t i n i b i s r e s t r i c t ed by Cy p3a , bu t no t by mAb c g2 o r mAb c b1a / 1b Ponatinib is given orally to patients. We therefore investigated the single and combined effect of mAbcg2 and mAbcb1a/1b deficiency on ponatinib (10 mg/kg) oral availability and tissue disposition over 24 h in wild-type (WT), Abcg2 -/- , Abcb1a/1b -/- and Abcb1a/1b;Abcg2 -/- mice (Figure 2A). We further investigated the impact of CYP3A-mediated metabolism on ponatinib kinetics using Cyp3a -/- mice, as the active ponatinib metabolite DMP is primarily formed by CYP3A4 [1, 16]. Neither single nor combined absence of Abcg2 and/or Abcb1a/1b resulted in a significant change in the oral availability of ponatinib during the first 24 h after oral intake (Figure 2A, Table 1). Absence of Cyp3a, however, did result in a significant 1.4-fold increase in plasma AUC 0- 24 relative to wild-type mice ( P = 0.0026), and Abcb1a/1b -/- ;Abcg2 -/- mice ( P = 0.0168) (Figure 2A, Table 1). Figure 2. Plasma concentration-time curves of ponatinib in female WT (black circles), Abcg2 -/- (green triangles), Abcb1a/1b -/- (red triangles), Abcg2;Abcb1a/1b -/- (blue squares) and Cyp3a -/- mice (yellow diamonds) over 24 hours (A) or 2 hours (B) after oral administration of 10 mg/kg ponatinib. Data are given as mean ± SD (SD rendered one-sided for improved clarity). n = 4-5 mice per group. Plasma concentration (ng/ml) 0 4 8 12 16 20 24 0 100 200 300 Time (h) Cyp3a-/- Wild-type Abcb1a/1b;Abcg2-/- Abcb1a/1b-/- Abcg2-/- A B 0.0 0.5 1.0 1.5 2.0 0 100 200 300 400 500 Time (h) Plasma concentration (ng/ml) Abcb1a/1b;Abcg2-/- Abcb1a/1b-/- Abcg2-/- Wild-type Figure 2 - Plasma concentration-time curves of ponatinib in female WT (black circles), Abcg2 -/- (green triangles), Abcb1a/1b -/- (red triangles), Abcg2;Abcb1 /1b -/- (blue squares) and Cyp3a -/- mice (yellow diamonds) over 24 hours (A) or 2 hours (B) after oral administration of 10 mg/kg ponatinib. Data are given as mean ± SD (SD rendered one-sided for improved clarity). n = 4-5 mice per group.