Factors associated with thiopurines’ metabolites level

Abstract

Abstract Introduction: Tioguanine nucleotides (6-TGN) and 6-methylmercaptopurine ribonucleotides (6-MMPR) are metabolites of azathioprine (AZA) and 6-mercaptopurine (6-MP) and are respectively associated with therapy response and hepatotoxicity. That is why some international associations recommend reactive therapeutic drug monitoring (TDM) in IBD patients. To help identifying patients suitable for proactive TDM we want to identify independent factors associated with 6-TGN and 6-MMPR levels and if sex is one of these independent factors which is associated with 6-MMPR levels.

Methods: In this retrospective cohort study, patients with AZA or 6-MP use and measurements of 6-TGN and 6-MMPR from 1 June 2016 till 1 February 2023 were included. Simple linear and logistic regression analysis were used to identify factors with a p-value <0.10 associated respectively with 6-TGN and 6-MMPR >5700 pmol/8 x 108 RBCs. These factors were then further analyzed with multiple linear and logistic regression analyses. Patients using AZA and 6-MP were separately examined.

Results: There were 270 patients included in this study. Log-transformed 6-TGN was associated with prescribed daily dose of AZA (B = 0.002, P = 0.035) mesalazine use (B = 0.226, P = 0.038), age (B = -0.010, P < 0.001) and leucocytes (B = -0.040, P = 0.007) in patients using AZA after multiple linear regression analysis. Log-transformed 6-TGN was associated with weight (B = -0.017, P = 0.001), MCV (B = 0.041, P = 0.017) and RDW (B = 0.107, P = 0.007) in patients using 6-MP after multiple linear regression analysis. Only in patients using AZA 6-MMPR >5700 pmol/8 x 108 RBCs had associations and were with prescribed daily dose of AZA (OR = 1.019, P < 0.001), age (OR = 1.034, P = 0.008) and thrombocytes (OR = 1.010, P < 0.001).

Conclusion: The results found in this study may have useful implications for earlier detecting patients suited for proactive TDM which may lead better therapy outcomes.