Akimitsu Maeda1, Hitoshi Ando2, Kei Irie3,4, Naoya Hashimoto5, Jun-Ichi Morishige2, Shoji Fukushima3, Akira Okada6, Hiromichi Ebi7, Masahide Matsuzaki5, Hiroji Iwata8, Masataka Sawaki8. 1. Department of Pharmacy, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan. m.akimitsu@aichi-cc.jp. 2. Department of Cellular and Molecular Function Analysis, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan. 3. Department of Pharmaceutics, Faculty of Pharmaceutical Science, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, 650-8586, Japan. 4. Department of Pharmacy, Kobe City Hospital Organization, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-minami-machi, Chuo-ku, Kobe, 650-0047, Japan. 5. Department of Pharmacy, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan. 6. Department of Regulatory Science, Faculty of Pharmacy, Musashino University, 1-1-20 Shinmachi , Nishitokyo City, 202-8585, Japan. 7. Division of Molecular Therapeutics, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan. 8. Department of Breast Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan.
Abstract
PURPOSE: Adverse events after the use of the CDK4/6 inhibitor abemaciclib are dose-dependent. However, its pharmacokinetics varies among individuals. Abemaciclib is reportedly transported by P-glycoprotein and breast cancer resistance protein. Therefore, we evaluated whether ABCB1 and ABCG2 polymorphisms are pharmacokinetic predictive factors of abemaciclib. METHODS: A total of 45 patients with breast cancer taking abemaciclib (150 mg twice per day) for 2 weeks were evaluated to determine the associations among abemaciclib concentration; adverse events; and ABCB1 1236 T > C, 2677G > T/A, 3435C > T, and ABCG2 421C > A gene polymorphisms. RESULTS: The trough concentration of abemaciclib was significantly higher in the group with grade 2 or greater neutropenia and thrombocytopenia than in those with grades 0 or 1. For ABCB1 2677G > T/A polymorphisms, the concentration of abemaciclib tended to be higher in the homozygous group (TT + AT) than in the wild-type + heterozygous group (GG + GA + GT) (median [range], 222.8 [80.5-295.8] ng/mL vs. 113.5 [23.6-355.2] ng/mL, P = 0.09), Moreover, the ABCB1 2677G > T/A homozygous group had a higher tendency of abemaciclib withdrawal or dose reduction within 4 weeks than the wild-type + heterozygous group (odds ratio, 4.22; 95% confidence interval, 0.86-20.7; P = 0.08). No significant association was observed among abemaciclib concentration; adverse reactions; and ABCB1 1236 T > C, 3435C > T, and ABCG2 421C > A polymorphisms. CONCLUSION: ABCB1 2677G > T/A polymorphism might be a predictor of the pharmacokinetics and tolerability of abemaciclib.
PURPOSE: Adverse events after the use of the CDK4/6 inhibitor abemaciclib are dose-dependent. However, its pharmacokinetics varies among individuals. Abemaciclib is reportedly transported by P-glycoprotein and breast cancer resistance protein. Therefore, we evaluated whether ABCB1 and ABCG2 polymorphisms are pharmacokinetic predictive factors of abemaciclib. METHODS: A total of 45 patients with breast cancer taking abemaciclib (150 mg twice per day) for 2 weeks were evaluated to determine the associations among abemaciclib concentration; adverse events; and ABCB1 1236 T > C, 2677G > T/A, 3435C > T, and ABCG2 421C > A gene polymorphisms. RESULTS: The trough concentration of abemaciclib was significantly higher in the group with grade 2 or greater neutropenia and thrombocytopenia than in those with grades 0 or 1. For ABCB1 2677G > T/A polymorphisms, the concentration of abemaciclib tended to be higher in the homozygous group (TT + AT) than in the wild-type + heterozygous group (GG + GA + GT) (median [range], 222.8 [80.5-295.8] ng/mL vs. 113.5 [23.6-355.2] ng/mL, P = 0.09), Moreover, the ABCB1 2677G > T/A homozygous group had a higher tendency of abemaciclib withdrawal or dose reduction within 4 weeks than the wild-type + heterozygous group (odds ratio, 4.22; 95% confidence interval, 0.86-20.7; P = 0.08). No significant association was observed among abemaciclib concentration; adverse reactions; and ABCB1 1236 T > C, 3435C > T, and ABCG2 421C > A polymorphisms. CONCLUSION: ABCB1 2677G > T/A polymorphism might be a predictor of the pharmacokinetics and tolerability of abemaciclib.
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