Thiopurines’ Metabolites and Drug Toxicity: A Meta-Analysis

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.

Liver-side of inflammatory bowel diseases: Hepatobiliary and drug-induced disorders

“…Approximately 15%–20% of IBD patients treated with thiopurines demonstrate hypermethylation (or shunting), a phenomenon due to a high TPMT activity that leads to preferential methylation of 6-MP to 6-MMP over bioactivation to thioguanine nucleotides (TGNs); the usual definition of hypermethylation is a ratio of 6-MMP to TGNs of > 11. Subtherapeutic TGNs level results in a poor response to therapy, while a high 6-MMP level (> 5700 pmol/8 × 10 8 erythrocytes) has been correlated with a 3-fold increased risk of liver toxicity[ 115 ]. Allopurinol is a xanthine oxidase inhibitor that prevents the breakdown of thiopurines into thiouric acid (TUA), thus increasing the bioavailability of 6-MP.…”

“…Moreover, a recent case-control study and a meta-analysis failed to demonstrate any correlations between TPMT gene polymorphisms and hepatic adverse events in IBD patients[ 119 , 120 ]. The reported frequency of thiopurine-related hepatotoxicity varies widely among studies, ranging from to 3% to 17%[ 108 , 115 , 121 , 122 ]; a systematic review by Gisbert et al [ 113 ] reported a mean prevalence of thiopurine-induced liver injury of 3%, with a mean annual rate of 1.4%[ 113 ]. In a prospective cohort study, abnormal liver function (defined by ALT or ALP levels > 50% the upper normal limit) occurred in 13% of patients, while hepatotoxicity (defined by ALT or ALP levels greater than twice the upper normal limit) developed in 10%[ 111 ].…”

Thiopurines in Inflammatory Bowel Disease. How to Optimize Thiopurines in the Biologic Era?

“…High levels of MMP have been associated with thiopurinerelated hepatotoxicity (91)(92)(93). Moreover, in one study, patients with MMP levels between 3,615 and 5,700 pmol/8 × 10 8 RBC had a 4-fold risk of hepatotoxicity (85); however, subsequent studies did not confirm this association (21). In fact, in one study almost 90% of patients with high concentration of MMP did not develop hepatotoxicity and, in 40% of patients with hepatotoxicity, MMP levels were below the risk cutoff (21).…”

“…It has been suggested that the TGN target levels are likely to depend on the situation. When TP are used as monotherapy, TGN levels above 230-235 pmol/8 × 10 8 RBC have been associated with clinical response, and more than 450 pmol/8 × 10 8 RBC have been associated with an increased risk of myelotoxicity (5,85). Regarding mucosal healing, a cutoff level of 397 pmol/8 × 10 8 RBC has been proposed with high specificity but low sensibility (86.7 and 35.3%, respectively) (86).…”

Advances in Thiopurine Drug Delivery: The Current State-of-the-Art

“…Another meta-analysis also showed that higher 6-TGN levels were present in patients with leukopenia (mean difference 127.1 pmol/8 × 10 8 RBC) and gastrointestinal intolerance (201.5 pmol/8 × 10 8 RBC). Furthermore, 6-methylmercaptopurine ribonucleotides (6-MMPR) were significantly associated with hepatoxicity (mean difference 3241.2 pmol/8 × 10 8 RBC; OR 4.28 [95% CI 3.20–5.71] [ 35 ]. Therefore, achieving adequate 6-TGN levels is clinically relevant for IBD patients.…”