Metabolite monitoring to guide thiopurine therapy in systemic autoimmune diseases

Abstract

6-Thioguanine nucleotide (6-TGN) is the active metabolite of thiopurine drugs azathioprine and 6-mercaptopurine. 6-Methylmercaptopurine (6-MMP) is an inactive and potentially hepatotoxic metabolite. A subgroup of patients (shunters) preferentially produce 6-MMP instead of 6-TGN, therefore displaying thiopurine resistance and risk for hepatotoxicity. Outside inflammatory bowel disease literature, few data exist regarding individualized thiopurine therapy based on metabolite monitoring. This study sought to describe metabolite monitoring in patients receiving weight-based thiopurine for systemic autoimmune diseases. Patients were enrolled using a laboratory database, and data were retrospectively collected. The correlation between the highest thiopurine dose (mg/kg) and the 6-TGN concentration (pmol/8 × 10 erythrocytes) was estimated with Pearson's correlation coefficient. Seventy-one patients with various systemic autoimmune conditions were enrolled. The correlation between the thiopurine dose and the 6-TGN level was weak for the overall patient sample (r = 0.201, p = 0.092) and for the subgroup of non-shunters (r = 0.278, p = 0.053). Subjects with 6-MMP levels >5700 pmol/8 × 10 erythrocytes had more hepatic cytolysis compared to subjects with 6-MMP <5700, OR = 4.36 (CI 95% 1.18-16.13, p = 0.027). Twenty-two patients (31%) were identified as shunters. Six shunters developed hepatotoxicity, five of which had 6-MMP concentration >5700. Eleven non-shunters had hepatotoxicity, one of which had 6-MMP >5700. Thiopurine metabolite monitoring shows wide variability in 6-TGN levels among patients treated with weight-based thiopurine for systemic autoimmune diseases. Thirty-one percent of the patients in our series fulfilled the shunter definition. Thiopurine metabolite monitoring and dose adjustment to improve maintenance of remission and avoid hepatotoxicity should be studied prospectively.

Persistent Mixed Cryoglobulinemia Despite Successful Treatment of Hepatitis C, Aggressive B-Cell–Directed Therapies, and Long-term Plasma Exchanges

“…Thiopurine S-methyltransferase activity was tested prior to eliminate a deficiency, which would increase the risk of toxicity. Reactive thiopurine metabolites were monitored to guide therapy dosing and avoid adverse effects due to thiopurine toxicity (targeted 6-thioguanine, levels between 230 and 450 pmol/8 × 10 8 erythrocytes, and 6-methylmercaptopurine, levels <5700 pmol/8 × 10 8 erythrocytes to avoid hepatotoxicity) 8 . The azathioprine dose was progressively increased to 350 mg daily (2.8 mg/kg), respecting these thresholds and under this therapy, his glomerular filtration rate stabilized and his RF and proteinuria remained low (Figure 2); however, he never normalized his C4 and remained PLEX dependent, as evidenced by his recurrent purpura.…”

Thiopurines’ Metabolites and Drug Toxicity: A Meta-Analysis

“…Our analysis showed that there was no significant association between 6-MMPR/6-TGN ratio (thresholds of 20 [ 57 ] and 24 [ 82 ]) and liver toxicity (OR 2.9, 95% CI 0.74; 11.55; p = 0.13) ( p = 0.03; I 2 = 80%).…”

“…In a pooled analysis of 22 reports [ 40 , 46 , 48 , 56 , 57 , 58 , 65 , 67 , 70 , 72 , 73 , 75 , 84 , 85 , 91 , 92 , 94 , 96 , 98 , 103 , 105 , 107 ], 6-TGN concentrations were significantly higher in patients with leukopenia (mean difference of 127.06 pmol/8 × 10 8 RBC (95% CI 70.88; 183.24; p < 0.01)). We could observe a considerable heterogeneity between studies ( p < 0.01; I 2 = 90%).…”

“…Nine studies provided data for the calculation of a pooled OR [ 14 , 36 , 44 , 50 , 57 , 75 , 82 , 102 , 104 ]. It was possible to conclude that patients with 6-MMPR levels above the defined thresholds, ranging from 3615 to 5700 pmol/8 × 10 8 RBC, were about four times more likely to develop hepatotoxicity ( Figure 5 c).…”

Arzneimittelnebenwirkungen in der Gastroenterologie

“…Immerhin geschieht bei einem Drittel der mit Azathioprin behandelten CED-Patienten eine solche Verschiebung des Metabolismus hin zum 6MMP [5]. Daher kann bei ausbleibendem Therapieerfolg oder bei Erhöhung der Transaminasen die Bestimmung der Thiopurinmetabolite im peripheren Blut die weitere Therapie relevant optimieren [6]. So sind 6TGN-Spiegel > 235 pmol/8 × 10 8 Erythrozyten mit einem Therapieerfolg assoziiert, wohingegen 6MMP-Spiegel > 5700 pmol/8 × 10 8 Erythrozyten eine Hepatotoxizität auslösen können (d. h. Hepatotoxizität bei einem Quotienten 6MMP/6TGN > 24) [4].…”