Association of axitinib plasma exposure and genetic polymorphisms of ABC transporters with axitinib-induced toxicities in patients with renal cell carcinoma

Axitinib is a selective tyrosine kinase inhibitor of VEGF receptors, approved for advanced renal cell carcinoma (RCC). Associations between axitinib plasma exposure, genetic polymorphisms of ABC transporters and axitinib-induced toxicities have not been adequately explored.

Twenty RCC patients treated with axitinib were enrolled in this study. Blood samples were collected 0, 0.5, 1, 2, 4, and 6 h after administration of axitinib on day 1 and at steady state. Plasma concentrations of axitinib were analyzed by UPLC-MS/MS. The ABCG2 (421C>A) and ABCB1 (1236C>T, 2677G>T/A, 3435C>T) genetic polymorphisms were determined by real-time PCR.

ABCB1 haplotype was associated with increased dose-adjusted area under the plasma concentration-time curve (AUC) of axitinib at steady state. The incidence of fatigue during therapy was associated with high AUC0-6 of axitinib (P = 0.013). The treatment period without discontinuation or dose reduction due to adverse events in patients with high AUC0-6 of axitinib was significantly shorter than for those with low AUC0-6 (P = 0.024). No significant differences were found in the frequency of adverse events among the ABCG2 genotype and ABCB1 haplotype groups.

Our results have demonstrated that adverse events leading to discontinuation or dose reduction in axitinib were associated with increased axitinib plasma exposure, but not directly with genetic polymorphisms of ABC transporters. Therefore, measurement of steady state axitinib plasma concentrations may be useful in avoiding adverse events in axitinib therapy.

Cancer chemotherapy and pharmacology. 2016 Sep 01 [Epub ahead of print]

Hiroshi Kato, Naoto Sassa, Masayuki Miyazaki, Mio Takeuchi, Miho Asai, Akane Iwai, Yukihiro Noda, Momokazu Gotoh, Kiyofumi Yamada

Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan. ., Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8560, Japan., Division of Clinical Sciences and Neuropsychopharmacology, Meijo University Faculty of Pharmacy, Nagoya, Japan.