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) 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 = .026, .012 and .015, respectively). The median (95% confidence interval) CSF4 -to-C4 ratio of ponatinib in 4 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 = .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.

• Authors: Yayoi Fukushi, Yumiko Akamine, Maiko Abumiya, Nagi Tozawa, Takaya Yamashita, Miho Nara, Yoshihiro Kameoka, Naoto Takahashi, Masatomo Miura
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 89 Issue 5 Pg. 1695-1700 (05 2023) ISSN: 1365-2125 [Electronic] England
• PMID: 36541130 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 British Pharmacological Society.

Chemical References

• ponatinib
• ATP Binding Cassette Transporter, Subfamily B
• ABCB1 protein, human

Topics

• Humans
• Philadelphia Chromosome
• East Asian People
• ATP Binding Cassette Transporter, Subfamily B (genetics)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics)
• Polymorphism, Single Nucleotide