Comparison Of Pharmacodynamics Of Methotrexate As Methotrexate-Polyglutamates Concentrations In Rheumatoid Arthritis; Interim Data Evaluation Of Miracle Study Conducted In Japan, Korea And Taiwan

Background:Methotrexate (MTX) is the first-line therapy for rheumatoid arthritis (RA). The concentrations of MTX-polyglutamates (PG) in erythrocytes, an active form of MTX, are useful markers for the optimal usage of MTX in patients with RA. The concentrations of MTX-PG have been reported to be different between Japanese and Caucasians. However, the difference among Asian ethnicity remains unclear.Objectives:To examine MTX-PG concentrations in association with MTX dose during the first 24 weeks after the initiation of MTX for newly diagnosed RA patients in Japan, Korea and Taiwan.Methods:MIRACLE study is a multicenter, open-label, randomized, 48 weeks interventional study conducted in Japan, Korea and Taiwan to evaluate non-inferiority of low dose to high dose of MTX as an add-on therapy to adalimumab in 300 patients with RA who do not achieve remission after 24 weeks MTX monotherapy in stipulated dosage. In the first 24 weeks, MTX was started at 6 to 8 mg/week for newly diagnosed RA patients, and promptly escalated to the maximum tolerable dose in 12 weeks in principle. This interim data evaluation was intended to investigate the differences among countries in the relationship between MTX dose, safety and MTX-PG concentrations in erythrocytes during the first 24 weeks. The efficacy of the treatment is not included at this point.Results:A total of 166 patients (106 in Japan, 35 in Korea, 25 in Taiwan) were included in this interim data. The age at treatment initiation was 57.2 years old on average and female was 79.5%. The time course changes in total and individual MTX-PG levels differed in the three countries. At 24 weeks, whereas the mean total MTX-PG concentrations were comparable (112.9 nmol/L in Japan, 104.4 nmol/L in Korea, and 115.7 nmol/L in Taiwan) with a dose of MTX of 12.3 mg/week, 14.1 mg/week, and 12.2 mg/week, respectively, the individual MTX-PG concentrations were different. The MTX-PG1 and MTX-PG2 concentrations were lower in Korea than Japan and Taiwan whereas MTX-PG3, MTX-PG4 and MTX-PG5 concentrations were the highest in Korea.Conclusion:The distribution of short-chain and long-chain MTX-PG concentrations were various among Asian countries despite similar dose of MTX administration: NCT03505008.Disclosure of Interests:Hiroya Tamai: None declared, Yuko Kaneko Speakers bureau: AbbVie, Astellas, Ayumi, Bristol–Myers Squibb, Chugai, Eisai, Eli Lilly, Hisamitsu, Jansen, Kissei, Kirin, Pfizer, Sanofi, Takeda, Tanabe-Mitsubishi, and UCB., Grant/research support from: Sanofi, Hideto Kameda Speakers bureau: AbbVie, Pfizer, Consultant of: AbbVie, Grant/research support from: AbbVie, Eisai, Masataka Kuwana Speakers bureau: Astellas, Asahi Kasei Pharma, Boehringer- Ingelheim, Chugai, Eisai, Janssen, Mochida, Nippon Shinyaku, Ono Pharmaceuticals, Pfizer, Mitsubishi-Tanabe, Consultant of: Corbus, Grant/research support from: AbbVie, Asahi Kasei Pharma, Boehringer- Ingelheim, Chugai, Eisai, MBL, Nippon Shinyaku, Ono Pharmaceuticals, Mitsubishi-Tanabe, Yutaka Okano: None declared, Tomonori Ishii Speakers bureau: Chugai, Mitsubishi- Tanabe, Glaxo Smith Kline, Pfizer, Eli Lilly, Janssen, AbbVie, Eisai, Astellas, Kei Ikeda Speakers bureau: AbbVie, Eli Lilly, Novartis, Mitsubishi-Tanabe, Eisai, BMS, Grant/research support from: Mitsubishi-Tanabe, Hiroaki Taguchi: None declared, Shinji Sato: None declared, Toshiaki Miyamoto: None declared, Shintaro Hirata Speakers bureau: AbbVie, Asahi Kasei Pharma, Astellas, Ayumi, Bristol Myers Squibb, Chugai, Eisai, Eli Lilly, Janssen, Glaxo Smith Kline, Kissei, Pfizer, Sanofi, Mitsubishi- Tanabe, UCB, Paid instructor for: AbbVie, Mitsubishi- Tanabe, Consultant of: AbbVie, Eisai, Gilead, Grant/research support from: AbbVie, Chugai, Mitsubishi-Tanabe, UCB, Hidekata Yasuoka Speakers bureau: AbbVie, Asahi Kasei Pharma, Astellas, Daiichi- Sankyo, Eisai, Kissei, Takeda, Mitsubishi- Tanabe, Chugai, Novartis, Eli Lilly, Pfizer, Janssen, Sanofi, Teijin, Boehringer- Ingelheim, Bayer, Glaxo Smith Kline, Paid instructor for: AbbVie, Consultant of: AbbVie, Asahi Kasei, Grant/research support from: Mitsubishi-Tanabe, Takeda, Daiichi-Sankyo, Chugai, Bristol-Myers, MSD, Astellas, Toshihisa Kojima Speakers bureau: AbbVie, Pfizer, Eisai, Grant/research support from: AbbVie, Sung-Hwan Park: None declared, Kichul Shin: None declared, Han Joo Baek: None declared, Yun Jong Lee Grant/research support from: research fund, In Ah Choi Speakers bureau: Abbvie, Eizai, Grant/research support from: Abbvie, Eizai, Jinhyun Kim: None declared, Ping-Ning Hsu: None declared, Chang-Fu Kuo: None declared, Chun-Ming Huang Paid instructor for: AbbVie, Pfizer, Meng-Yu Weng Consultant of: AbbVie, Wan-Yu Sung: None declared, Wen-Chan Tsai: None declared, Tien-Tsai Cheng Paid instructor for: AbbVie, Grant/research support from: AbbVie, Takehiro Taninaga Shareholder of: Eisai Co., Ltd., Employee of: Eisai Co., Ltd., Masahiko Mori Shareholder of: Eisai Co., Ltd., Employee of: Eisai Co., Ltd., Hideaki Miyagishi Employee of: Eisai Co., Ltd., Yasunori Sato: None declared, Tsutomu Takeuchi Speakers bureau: Astellas, Abbvie, Daiichi Sankyo, Ayumi, Eisai, GlaxoSmithKline, Mitsubishi Tanabe, Chugai, Novartis, Eli Lilly, Pfizer, Bristol Myers Squibb, Janssen, UCB, TaishoToyama, Sanofi–Aventis, Nipponkayaku, Taiho, Gilead, Boehringer Ingelheim, Grant/research support from: Asahikasei, Astellas, Abbvie, Daiichi Sankyo, Ayumi, Eisai, Takeda, Mitsubishi Tanabe, Chugai, Eli Lilly, UCB, Sanofi–Aventis, Nipponkayaku, Boehringer Ingelheim