Therapeutic drug monitoring of thiopurine metabolites in adult thiopurine tolerant IBD patients on maintenance therapy

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• 作者：Lennard P.L. Gilissen^a ; ¹ ; ^{lennard.gilissen@cze.nl} ; Dennis R. Wong^b ; ¹ ; ^{d.wong@orbisconcern.nl} ; Leopold G.J.B. Engels^c ; ^{l.engels@orbisconcern.nl} ; Jö ; rgen Bierau^d ; ^{jorgen.bierau@mumc.nl} ; Jaap A. Bakker^d ; ^{jaap.bakker@mumc.nl} ; Aimé ; e D.C. Paulussen^d ; ^{aimee.paulussen@mumc.nl} ; Marië ; lle J. Romberg-Camps^c ; ^{m.camps@orbisconcern.nl} ; Arnold Stronkhorst^a ; ^{arnold.stronkhorst@cze.nl} ; Paul Bus^e ; ^P.Bus@lzr.nl ; Laurens P. Bos^c ; ^{r.bos@orbisconcern.nl} ; Piet M. Hooymans^b ; ^{p.hooymans@orbisconcern.nl} ; Reinhold W. Stockbrü ; gger^h ; ^{rstockbrugger635@gmail.com} ; Cees Neef^f ; ^g ; ^{c.neef@mumc.nl} ; Ad A.M. Masclee^h ; ^{a.masclee@mumc.nl}
• 关键词：AZA ; azathioprine ; CAI ; Colitis Activity Index ; CDAI ; Crohn's Disease Activity Index ; CI 95% ; 95%confidence interval ; HPLC ; high performance liquid chromatography ; IBD ; inflammatory bowel disease ; 6-MMPR ; 6-methylmercaptopurine ribonucleotides ; 6-MP ; 6-m
• 刊名：Journal of Crohn's and Colitis
• 出版年：2012
• 期刊代码：pca215_18739946
• 类别：med
• 出版时间：July, 2012
• 卷：6
• 期：6
• 页码：698-707
• 文件大小：546 K

摘要

Background and aims

Therapeutic drug monitoring of active metabolites of thiopurines, azathioprine and 6-mercaptopurine, is relatively new. The proposed therapeutic threshold level of the active 6-thioguanine nucleotides (6-TGN) is 鈮?#xA0;235 pmol/8 脳 10⁸ erythrocytes. The aim of this prospective cross-sectional study was to compare 6-TGN levels in adult thiopurine tolerant IBD patients with an exacerbation with those in remission, and to determine the therapeutic 6-TGN cut-off level.

Methods

Hundred IBD patients were included. Outcome measures were thiopurine metabolite levels, calculated therapeutic 6-TGN cut-off level, CDAI/CAI scores, thiopurine dose and TPMT enzyme activity.

Results

Forty-one patients had an exacerbation, 59 patients were in remission. In 17%of all patients 6-TGN levels were compatible with non-compliance. The median 6-TGN levels were not significantly different between the exacerbation and remission group (227 versus 263 pmol/8 脳 10⁸ erythrocytes, p = 0.29). The previous reported therapeutic 6-TGN cut-off level of 235 pmol/8 脳 10⁸ erythrocytes was confirmed in this study. Twenty-six of the 41 patients (63%) with active disease had 6-TGN levels below this threshold and 24 of 59 IBD patients (41%) in clinical remission (p = 0.04).

Conclusions

Thiopurine non-compliance occurs frequently both in active and quiescent disease. 6-TGN levels below or above the therapeutic threshold are associated with a significant higher chance of IBD exacerbation and remission, respectively. These data support the role of therapeutic drug monitoring in thiopurine maintenance therapy in IBD to reveal non-compliance or underdosing, and can be used as a practical tool to optimize thiopurine therapy, especially in case of thiopurine non-response