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Poster presentations: Clinical: Therapy and Observation 2020

P478 Thiopurines’ metabolites levels and drug toxicity: a systematic review and meta-analysis

P.C. Sousa1, M. Estevinho2, C.C. Dias3, D. Martins1, E. Cancela1, F. Pires1, C. Carvalho1, P. Ministro1, F. Magro2

1Department of Gastroenterology, Centro Hospitalar Tondela-Viseu, Viseu, Portugal, 2Department of Biomedicine, University of Porto, Oporto, Portugal, 3Faculty of Medicine of University of Porto, Unit of Pharmacology and Therapeutics, Oporto, Portugal

Background

Besides Inflammatory Bowel Disease, thiopurines are used in a broad range of clinical conditions. Even though therapeutic drug monitoring (TDM) is widely used with biologics, there are still many unanswered questions regarding TDM for thiopurines. This study aimed to establish a relationship between the levels of thiopurines’ metabolites and treatment toxicity.

Methods

Literature search was carried out in 3 databases (Pubmed, Web of Science and Scopus) following PRISMA guidelines. Studies evaluating the relationship between the levels of thiopurines’ metabolites and their toxicity (haematological and hepatoxicity, pancreatitis, intolerance and infection), regardless of the disease to which they were prescribed, were included.

Results

From the 16194 identified records 74 were eligible for further analysis. A meta-analysis of mean comparisons, correlations and odds ratio (OR) were performed. The levels of 6-thioguanine nucleotides (6-TGN) were significantly higher in patients with general toxicity and leukopenia when the Lennard method was used for quantification (Figure 1). Significant correlations were obtained between the 6-TGN levels and leucocytes (r = -0.21;p < 0.001), neutrophils (r = -0.34;p < 0.001) and alanine aminotransferase (ALT) levels (r = -0.24;p < 0.001). The pooled OR (95%IC) for general toxicity, haematological toxicity and leukopenia in patients with 6-TGN concentrations above the predefined thresholds was 2.78(1.54–5.00), 8.54(3.55–20.56) and 5.26(3.34–8.15), respectively. Regarding 6-methylmercaptopurine metabolites (6-MMP), there was a significant correlation of their levels with general toxicity and leukopenia when the Lennard method was used for quantification (Figure 2), and with hepatotoxicity. 6-MMP levels were significantly correlated with ALT (r = 0.35;p < 0.001). The pooled OR (95%IC) for haematological toxicity, leukopenia and hepatotoxicity in patients with 6-MMP above the predefined thresholds was 4.12(1.80–9.47), 4.09(1.98–8.45) and 4.31(3.21–5.78), respectively. The studies evaluating the relationship between the ratio 6-MMP/TGN and thiopurines’ toxicity did not find differences between the mean ratio in patients with haematological toxicity and leukopenia. The pooled OR for hepatotoxicity in patients with a ratio above the predefined threshold was 4.44(IC 95%2.92–6.75).

Figure 1. Mean differences between 6-TGN levels in patients with and without general toxicity(A) and leukopenia(B).

Figure 2. Mean differences between 6-MMP levels in patients with and without general toxicity(A) and leukopenia(B).

Conclusion

These results reinforce that TDM may be used to prevent the occurrence of toxicity during thiopurines’ treatment. However, the cut-off values for this association may depend on the method used to measure metabolites’ levels.