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P523 Association between pharmacokinetics of adalimumab and disease outcome in Japanese patients with biologics naïve Crohn's disease: a subanalysis of DIAMOND trial

Motoya S.*1, Nakase H.2, Matsumoto T.3, Watanabe K.4, Hisamatsu T.5, Yoshimura N.6, Ishida T.7, Kato S.8, Nakagawa T.9, Nagahori M.10, Esaki M.11, Matsui T.12, Naito Y.13, Kanai T.14, Suzuki Y.15, Nojima M.16, Watanabe M.10, Hibi T.17 the DIAMOND Study Group

1Sapporo Kosei General Hospital, Inflammatory Bowel Disease Centre, Sapporo, Japan 2Sapporo Medical University School of Medicine, Department of Gastroenterology and Hepatology, Sapporo, Japan 3Iwate Medical University, Division of Gastroenterology, Department of Medicine, Morioka, Japan 4Osaka City General Hospital, Division of Gastroenterology, Osaka, Japan 5Kyorin University School of Medicine, Department of Internal Medicine, Tokyo, Japan 6Tokyo Yamate Medical Centre, Department of Medicine, Division of Gastroenterology, Tokyo, Japan 7Oita Red Cross Hospital, Department of Gastroenterology, Oita, Japan 8Saitama Medical University Saitama Medical Centre, Department of Gastroenterology and Hepatology, Kawagoe, Japan 9Chiba University School of Medicine, Department of Gastroenterology and Nephrology, Chiba, Japan 10Tokyo Medical and Dental University, Department of Gastroenterology and Hepatology, Tokyo, Japan 11Kyushu University Graduate School of Medical Sciences, Department of Medicine and Clinical Science, Fukuoka, Japan 12Fukuoka University Chikushi Hospital, Department of Gastroenterology, Chikushino, Japan 13Kyoto Prefectural University of Medicine, Department of Molecular Gastroenterology and Hepatology, Kyoto, Japan 14Keio University School of Medicine, Department of Internal Medicine, Tokyo, Japan 15Toho University Sakura Medical Centre, Department of Internal Medicine, Sakura, Japan 16University of Tokyo, Centre for Translational Research, Institute of Medical Science Hospital, Tokyo, Japan 17Kitasato University Kitasato Institute Hospital, Centre for Advanced IBD Research and Treatment, Tokyo, Japan

Background

Recently, we reported the result of a randomized clinical trial to compare the clinical efficacy of adalimumab (ADA) monotherapy with the combination of ADA with azathioprine (AZA) in induction of remission for Japanese patients with Crohn's Disease (CD) naïve to tumor necrosis factor (TNF) antagonists (DIAMOND trial). However, whether ADA trough levels and anti-ADA antibodies (AAA) were relevant to disease outcome remains unclear. The aim of this study is to evaluate the impact of ADA trough levels and AAA at 26weeks on clinical activity at 52 weeks and to examine the effect of AZA on ADA trough level in CD patients enrolled in DIAMOND trial.

Methods

In the preceding DIAMOND trial, 176 patients with active CD naïve to TNF antagonists were randomly assigned to either have ADA monotherapy or the combination therapy. The clinical efficacy was evaluated at Week 26 and 52. Clinical remission was defined as a CDAI score of less than 150 points. Serum samples from the patients in both groups at Week 26 were collected and trough levels of ADA and AAA were measured by using ELISA system. Also, blood samples were collected from patients in the combination group at Week 12, and processed to measurement of 6-TGN in red blood cells (RBCs). A multiple regression model was performed to identify factors independently related to trough levels of ADA and AAA at Week 26. Covariates included in the model were age, sex, body weight, the duration of the disease, disease location, previous surgery, presence of internal fistula, presence of anal fistula, smoking status and medication at entry.

Results

One hundred and fifty-one serum samples were analyzed from 176 patients enrolled in the study. Patients with clinical remission at 52 weeks had significantly higher trough level of ADA (7.7 μg/ml) at 26 weeks than those with active disease (5.4 μg/ml: p<0.001). Development of AAA at 26 weeks was significantly and positively associated with disease activity at 52weeks (p=0.021). A multivariate logistic regression model revealed that sex and low body weight were factors independently associated with high ADA trough level, and that male sex was associated with occurrence of AAA. There was a trend towards a higher 6TG level at 12 weeks in CD patients negative for AAA at 26 weeks (322 pmol/8×108 RBCs) than in those positive for it (137 pmol/8×108 RBCs), despite no significant difference of mean dose of AZA between AAA negative and positive group.

Conclusion

Higher trough levels of ADA and absence of AAA at 26 weeks obviously affected clinical activity at 52 Weeks in CD patients treated with ADA monotherapy or the combination therapy. A high 6TG concentration might be required for suppression of AAA.