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Effects of ABCB1 polymorphisms on the transport of ponatinib into the cerebrospinal fluid in Japanese Philadelphia chromosome-positive acute lymphoblastic leukaemia patients
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  • Yayoi Fukushi,
  • Yumiko Akamine,
  • Maiko Abumiya,
  • Nagi Tozawa,
  • Takaya Yamashita,
  • Miho Nara,
  • Yoshihiro Kameoka,
  • Naoto Takahashi,
  • Masatomo Miura
Yayoi Fukushi
Akita University

Corresponding Author:fukushiy@hos.akita-u.ac.jp

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Yumiko Akamine
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Maiko Abumiya
Akita University
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Nagi Tozawa
Akita University Graduate School of Medicine School of Medicine
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Takaya Yamashita
Akita University Graduate School of Medicine School of Medicine
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Miho Nara
Akita University Graduate School of Medicine School of Medicine
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Yoshihiro Kameoka
Akita University Graduate School of Medicine School of Medicine
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Naoto Takahashi
Akita University Graduate School of Medicine School of Medicine
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Masatomo Miura
Akita University Hospital
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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.
27 Oct 2022Submitted to British Journal of Clinical Pharmacology
28 Oct 2022Submission Checks Completed
28 Oct 2022Assigned to Editor
28 Oct 2022Review(s) Completed, Editorial Evaluation Pending
31 Oct 2022Reviewer(s) Assigned
29 Nov 2022Editorial Decision: Revise Minor
14 Dec 20221st Revision Received
14 Dec 2022Submission Checks Completed
14 Dec 2022Assigned to Editor
14 Dec 2022Review(s) Completed, Editorial Evaluation Pending
16 Dec 2022Editorial Decision: Accept