Effects of ABCB1 polymorphisms on the transport of ponatinib into the
cerebrospinal fluid in Japanese Philadelphia chromosome-positive acute
lymphoblastic leukaemia patients
Abstract
The effects of polymorphisms of ABCB1 and ABCG2 on the dose-adjusted
plasma trough concentrations and cerebrospinal fluid (CSF)-to-plasma
ratios of ponatinib were evaluated. Blood (C4) and CSF (CSF4)
concentrations at 4 h after administration were determined. The median
(95% confidence interval (CI)) CSF4-to-C4 ratio of ponatinib in
subjects homozygous for ABCB1 variants 1236T/T, 2677T/T+T/A, or 3435T/T
were significantly higher than that in a group of subjects with other
genotypes (P = 0.026, 0.012, and 0.015, respectively). The median (95%
CI) CSF4-to-C4 ratio of ponatinib in four patients with the combination
of ABCB1 variants 1236T/T-2677T/T+T/A-3435T/T was 2.62 (1.42 – 3.42)%;
this ratio was significantly higher than that in subjects with other
genotypes [1.08 (0.89 – 1.47)%; P = 0.006]. The brain distribution
of ponatinib was affected by ABCB1 polymorphisms and therefore seems to
be modulated by P-glycoprotein at the blood-brain and blood-CSF
barriers.
