Monitoring Thiopurine Metabolites in Korean Pediatric Patients with Inflammatory Bowel Disease

Abstract

PurposeThis study aimed to assess the role of thiopurine S-methyltransferase (TPMT) and 6-thioguanine nucleotide (6-TGN) as predictors of clinical response and side effects to azathioprine (AZA), and estimate the optimal AZA dose in Korean pediatric inflammatory bowel disease (IBD) patients.Materials and MethodsOne hundred and nine pediatric IBD patients in whom AZA treatment was required were enrolled. Thiopurine metabolites were monitored since September 2010. Among them, 83 patients who had prescribed AZA for at least 3 months prior to September 2010 were enrolled and followed until October 2011 to evaluate optimal AZA dose, adverse effects and disease activity before and after thiopurine metabolite monitoring.ResultsThe result of the TPMT genotype was that 102 patients were *1/*1 (wild type), four were *1/*3C, one was *1/*6, one was *1/*16 (heterozygote) and one was *3C/*3C (homozygote). Adverse effects happened in 31 patients pre-metabolite monitoring and in only nine patients post-metabolite monitoring. AZA dose was 1.4±0.31 mg/kg/day before monitoring and 1.1±0.46 mg/kg/day after monitoring (p<0.001). However, there were no statistical differences in disease activity during metabolite monitoring period (p=0.34). Adverse effects noticeably decreased although reduction of the AZA dose since monitoring.ConclusionTPMT genotype and thiopurine metabolite monitoring could be helpful to examine TPMT genotypes before administering AZA and to measure 6-TGN concentrations during prescribing AZA in IBD patients.

Thiopurine Methyltransferase Genotype Testing in Paediatric Patients in South Australia. A Retrospective Audit into Prescribing Practices.

“…This is similar to rates seen in other parts of the world [12][13][14][15][16]. There were no homozygous variant genotypes found in this cohort of patients.…”

“…The frequency of two inactive alleles Thiopurine Methyltransferase Genotype Testing in Paediatric Patients in South Australia: A Retrospective Audit into Prescribing Practices is 1% in the sub-Saharan African population, 0.3% for Caucasians and perhaps even lower for the Asians [12][13][14]. In a study of Korean paediatric patients with IBD, 5.5% were heterozygotes and 0.9% was homozygous [15]. In contrast, 7.8% of paediatric patients with IBD examined in a study from Slovakia were heterozygotes [16] In Chilean children with ALL the frequency of heterozygotes was 8% [17].…”

Thiopurine metabolite level and toxicity in Indians with inflammatory bowel disease

“…Many patients with high level tolerated this metabolite level. It is previously reported that Asians have higher likelihood of thiopurine toxicity 21, 34. We had lowest toxicity as compared with that reported in the literature and did not observe any hepatotoxicity.…”

“…At this dose, median 6‐TGN level was 213 pmol/8 × 10 8 RBCs in active disease and 173 pmol/8 × 10 8 RBCs in patients with remission 29. A still lower dose, that is 1.2 mg/kg body weight, was used by Koreans, wherein the mean 6‐TGN level was 328 pmol/8 × 10 8 RBCs 34. In our study, patients on low dose of AZA (mean dose: 1.13 mg /kg, n = 57) had mean 6‐TGN level of 288 ± 240 pmol/8 × 10 8 RBCs and median 6‐TGN level of 217 (224) pmol/8 × 10 8 RBCs.…”

“…At this dose, a high 6‐TGN level was obtained in 23% of patients, 49% had subtherapeutic level while 28% had a therapeutic level. The other studies in literature where measurement of thiopurine metabolites has been performed are shown in Table 2 27, 28, 29, 30, 31, 32, 33, 34, 35. The comparison of different studies is complicated by the fact that some have used mean, whereas others have used median dose and drug levels.…”