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Influence of CYP3A4/5 and ABC transporter polymorphisms on lenvatinib plasma trough concentrations in Japanese patients with thyroid cancer.

ABSTRACT: Lenvatinib is a substrate of cytochrome P450 (CYP) 3A and ATP-binding cassette (ABC) transporters. In this study, we aimed to evaluate how CYP3A4/5 and ABC transporter polymorphisms affected the mean steady-state dose-adjusted plasma trough concentrations (C0) of lenvatinib in a cohort of 40 Japanese patients with thyroid cancer. CYP3A4 20230G?>?A (*1G), CYP3A5 6986A?>?G (*3), ABCB1 1236C?>?T, ABCB1 2677G?>?T/A, ABCB1 3435C?>?T, ABCC2 -24C?>?T, and ABCG2 421C?>?A genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism. In univariate analysis, there were no significant differences in the mean dose-adjusted C0 values of lenvatinib between the ABCB1, ABCG2, and CYP3A5 genotypes. However, the mean dose-adjusted C0 values of lenvatinib in patients with the CYP3A4*1/*1 genotype and ABCC2 -24T allele were significantly higher than those in patients with the CYP3A4*1G allele and -24C/C genotype, respectively (P?=?0.018 and 0.036, respectively). In multivariate analysis, CYP3A4 genotype and total bilirubin were independent factors influencing the dose-adjusted C0 of lenvatinib (P?=?0.010 and 0.046, respectively). No significant differences were found in the incidence rates of hypertension, proteinuria, and hand-foot syndrome following treatment with lenvatinib between the genotypes of CYP3A4/5 and ABC transporters. Lenvatinib pharmacokinetics were significantly influenced by the CYP3A4*1G polymorphism. If the target plasma concentration of lenvatinib for efficacy or toxicity is determined, elucidation of the details of the CYP3A4*1G genotype may facilitate decision-making related to the appropriate initial lenvatinib dosage to achieve optimal plasma concentrations.

SUBMITTER: Ozeki T

PROVIDER: S-EPMC6443943 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Influence of CYP3A4/5 and ABC transporter polymorphisms on lenvatinib plasma trough concentrations in Japanese patients with thyroid cancer.

Ozeki Tomoko T Nagahama Mitsuji M Fujita Kazuma K Suzuki Akifumi A Sugino Kiminori K Ito Koichi K Miura Masatomo M

Scientific reports 20190401 1

Lenvatinib is a substrate of cytochrome P450 (CYP) 3A and ATP-binding cassette (ABC) transporters. In this study, we aimed to evaluate how CYP3A4/5 and ABC transporter polymorphisms affected the mean steady-state dose-adjusted plasma trough concentrations (C<sub>0</sub>) of lenvatinib in a cohort of 40 Japanese patients with thyroid cancer. CYP3A4 20230G > A (*1G), CYP3A5 6986A > G (*3), ABCB1 1236C > T, ABCB1 2677G > T/A, ABCB1 3435C > T, ABCC2 -24C > T, and ABCG2 421C > A genotypes were determ ...[more]

PMID: 30931962

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Dataset Information

Influence of CYP3A4/5 and ABC transporter polymorphisms on lenvatinib plasma trough concentrations in Japanese patients with thyroid cancer.

Publications

Influence of CYP3A4/5 and ABC transporter polymorphisms on lenvatinib plasma trough concentrations in Japanese patients with thyroid cancer.

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