Thiopurines’ metabolites and drug toxicity: A meta analysis

Many questions remain unanswered regarding therapeutic drug monitoring (TDM) utility with thiopurines. This study aims to establish a relationship between thiopurines’ metabolites and drug toxicity. We performed a systematic review with inclusion of studies evaluating the relationship between thiopurines’ metabolites and drug toxicity. Metaanalysis of mean difference (MD), correlations and odds ratio (OR) was performed. We identified 21,240 records, 72 of which were eligible for metaanalysis. Levels of 6thioguanine nucleotides (6TGN) were higher in patients with leukopenia (MD 127.06 pmol/8 × 10⁸ RBC) and gastrointestinal intolerance (MD 201.46 pmol/8 × 10⁸ RBC), and lower in patients with hepatotoxicity (MD −40.6 pmol × 10⁸ RBC). We established a significant correlation between 6TGN and leukocytes (r = −0.21), neutrophils (r = −0.24) and alanine aminotransferase levels (r = −0.24). OR for leukopenia in patients with elevated 6TGN was 4.63 (95%CI 2.24; 9.57). An optimal cutoff of 135 pmol/8 × 10⁸ RBC for leukopenia was calculated (sensitivity 75.4%; specificity 46.4%). 6methylmercaptopurine ribonucleotides (6MMPR) were significantly associated with hepatotoxicity (MD 3241.2 pmol/8 × 10⁸ RBC; OR 4.28; 95%CI 3.20; 5.71). Levels of 6MMPR measured in the first 8 weeks of treatment were associated with leukopenia. We conclude that TDM could be used to prevent thiopurines’ toxicity. As optimal metabolites level may vary according to indication, physicians may adapt posology to decrease toxicity without compromising efficacy.