Abstract

Objective: Crohn’s disease (CD) is a chronic inflammatory gastrointestinal disease with repeated cycles of exacerbation and remission. Infliximab (IFX), a chimeric anti-TNF-α monoclonal antibody, has been widely used for the treatment of CD. However, no study in Japanese CD patients receiving continuous IFX for more than 1 year has been reported. To avoid therapeutic failure during long-term administration in Japanese CD patients, we evaluated the variable factors of IFX pharmacokinetics and the optimal trough IFX concentration at 8 weeks after administration.
Materials and methods: Population pharmacokinetic (PPK) analysis was performed using the nonlinear mixed-effect model based on the IFX serum concentration in 832 samples from 121 patients. A one-compartment model was used to examine interindividual variability in the systemic clearance (CL) of intravenously administered IFX.
Results: PPK estimates (estimated value, RSE%) were total clearance (CL: 0.018 L/h, 9.1) and volumes of distribution (Vd: 7.35 L, 12.0). Interindividual variability for CL and Vd of 0.11 and 0.16, respectively, was found. Body weight, antibody to IFX (ATI), and albumin level were factors affecting the IFX CL. IFX CL was greater in the ATI-positive than in the ATI-negative group. CL was also greater in nonremission patients. There was a significant association between the predicted serum IFX trough concentration at 8 weeks and therapeutic response with long-term continuous administration (p < 0.05), with a higher concentration at 8 weeks seen in the remission group.
Conclusion: Using these variables including body weight, ATI, and albumin level, the IFX dose could be calculated for individual CD patients to achieve the optimal therapeutic range.

Author Details

Authors

• Katsuyoshi Matsuoka^{1, 6}
• Shunsuke Hamada²
• Mikiko Shimizu³
• Kosaku Nanki¹
• Shinta Mizuno¹
• Hiroki Kiyohara¹
• Mari Arai¹
• Shinya Sugimoto¹
• Yasushi Iwao⁴
• Haruhiko Ogata⁵
• Tadakazu Hisamatsu^{1, 7}
• Makoto Nagauma¹
• Takanori Kanai¹
• Mayumi Mochizuki²
• Masayuki Hashiguchi²

Departments

• ¹ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku,
• ² Division for Evaluation and Analysis of Drug Information, Faculty of Pharmacy, Keio University, Shibakoen, Minato-ku, Tokyo,
• ³ Department of Drug Metablism and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Aomori University, Kobata, Aomori,
• ⁴ Center for Preventive Medicine, and
• ⁵ Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo,
• ⁶ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Chiba, and
• ⁷ Third Department of Internal Medicine, Kyorin University School of Medicine, Shinkawa, Mitaka, Tokyo, Japan

Address


Masayuki Hashiguchi, PhD
Division for Evaluation and Analysis of Drug Information
Faculty of Pharmacy, Keio University
1-5-30 Shibakoen, Minato-ku, 1058512 Tokyo, Japan
Email: hashiguchi-ms@­​
pha.keio.ac.jp

Citation