Thiopurines' Metabolites and Drug Toxicity: A Meta-Analysis.

Paula Sousa,Paula Ministro,Fernando Magro,Uri Kopylov,Silvio Danese,Maria Manuela Estevinho,Cláudia Camila Dias,Laurent Peyrin-Biroulet

doi:10.3390/jcm9072216

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 × 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 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 × 108 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 × 108 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.

Highlights

Thiopurines (comprising azathioprine (AZA), 6-mercaptopurine (6-MP), and 6-thioguanine) have been used for over 5 decades in the treatment of a myriad of disorders, including acute lymphoblastic leukemia (ALL), inflammatory bowel disease (IBD), auto-immune hepatitis (AIH), and in the prophylaxis of rejection in organ transplant recipients [1].As prodrugs, thiopurines have a complex metabolism which leads to the formation of 6-thioguanine nucleotides (6-TGN)
The wide use of thiopurines has been hindered by their inherent toxicity, which may result in underdosing and lack of efficacy [5]
The measurement of thiopurines’ metabolites can give physicians a safer context for prescription, if the levels are kept in the therapeutic range and below toxic thresholds

Summary

Introduction

Thiopurines have a complex metabolism which leads to the formation of 6-thioguanine nucleotides (6-TGN). Other pathways compete with the production of the active metabolite 6-TGN, leading to the formation of 6-methylmercaptopurine (6-MMP) and 6-MMP ribonucleotides (6-MMPR). These metabolites can be determined by different methods, such as the Lennard [2] and Dervieux–Boulieu assays [3], that perform the measurement in red blood cells (RBC), with concentrations expressed as pmol/8 × 108 RBC. Toxicity is an important cause of treatment cessation; in IBD, about 15% of patients discontinue thiopurines due to adverse events [4,5]. The most worrisome adverse event of 6-thioguanine is liver nodular regenerative hyperplasia (NRH), which still detracts some physicians from its use [6]

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Methods

Conclusion