Thiopurines' Metabolites and Drug Toxicity: A Meta-Analysis

Autores da FMUP

• Claudia Camila Rodrigues Pereira Dias

  Autor

• Fernando José Magro Dias

  Autor

Participantes de fora da FMUP

• Sousa, P
• Estevinho, MM
• Ministro, P
• Kopylov, U
• Danese, S
• Peyrin-Biroulet, L

Unidades de investigação

• Biomedicina

• Recursos Comuns

  

  Investigador

  Guilhermina Maria Da Silva Rêgo

• RISE-Health

  

  Investigador

  Fernando Carlos De Landér Schmitt

Abstract

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. Meta-analysis of mean difference (MD), correlations and odds ratio (OR) was performed. We identified 21,240 records, 72 of which were eligible for meta-analysis. Levels of 6-thioguanine nucleotides (6-TGN) were higher in patients with leukopenia (MD 127.06 pmol/8 x 10(8)RBC) and gastrointestinal intolerance (MD 201.46 pmol/8 x 10(8)RBC), and lower in patients with hepatotoxicity (MD -40.6 pmol x 10(8)RBC). We established a significant correlation between 6-TGN and leukocytes (r = -0.21), neutrophils (r = -0.24) and alanine aminotransferase levels (r = -0.24). OR for leukopenia in patients with elevated 6-TGN was 4.63 (95% CI 2.24; 9.57). An optimal cut-off of 135 pmol/8 x 10(8)RBC for leukopenia was calculated (sensitivity 75.4%; specificity 46.4%). 6-methylmercaptopurine ribonucleotides (6-MMPR) were significantly associated with hepatotoxicity (MD 3241.2 pmol/8 x 10(8)RBC; OR 4.28; 95% CI 3.20; 5.71). Levels of 6-MMPR 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.

Keywords

• thiopurines; therapeutic drug monitoring; adverse events