PURPOSE: Thiopurine drugs have to be withdrawn in 10-30% of cases due to side effects, and it has been presented that genetic factors may be responsible for some of reported toxicity cases. Among polymorphic enzymes of thiopurines' metabolic pathway, thiopurine S-methyltransferase (TPMT) has been studied most extensively, and some recent studies point to inosine triphosphate pyrophosphohydrolase (ITPA) polymorphism as an additional toxicity risk factor. METHODS: The aim of the current study was to evaluate an association between TPMT and ITPA gene polymorphisms and drug intolerance in a cohort of 157 renal transplant recipients treated with azathioprine (AZA). Each subject was genotyped for the presence of variant TPMT (*2, *3A, *3B, and *3C) and ITPA (94C>A and IVS2+21A>C) alleles. RESULTS: Mean AZA dose, mean white-blood-cell count, and platelet count in the course of treatment were lower in carriers of variant TPMT alleles compared to patients with TPMT wild-type genotype. Leukocyte numbers fell below 4.0 x 10(9)/L in 41.2% of TPMT heterozygous renal transplant recipients, compared to only 18.0% of wild-type patients (P < 0.01). In contrast, ITPA genotype did not influence AZA dose, hematological parameters, or leucopenia risk. CONCLUSIONS: Our results suggest that routine genotyping of renal transplant recipients for TPMT variants may be useful in reducing the risk of AZA-related myelotoxicity, but there is not enough evidence to introduce ITPA testing into clinical practice.
PURPOSE:Thiopurine drugs have to be withdrawn in 10-30% of cases due to side effects, and it has been presented that genetic factors may be responsible for some of reported toxicity cases. Among polymorphic enzymes of thiopurines' metabolic pathway, thiopurine S-methyltransferase (TPMT) has been studied most extensively, and some recent studies point to inosine triphosphate pyrophosphohydrolase (ITPA) polymorphism as an additional toxicity risk factor. METHODS: The aim of the current study was to evaluate an association between TPMT and ITPA gene polymorphisms and drug intolerance in a cohort of 157 renal transplant recipients treated with azathioprine (AZA). Each subject was genotyped for the presence of variant TPMT (*2, *3A, *3B, and *3C) and ITPA (94C>A and IVS2+21A>C) alleles. RESULTS: Mean AZA dose, mean white-blood-cell count, and platelet count in the course of treatment were lower in carriers of variant TPMT alleles compared to patients with TPMT wild-type genotype. Leukocyte numbers fell below 4.0 x 10(9)/L in 41.2% of TPMT heterozygous renal transplant recipients, compared to only 18.0% of wild-type patients (P < 0.01). In contrast, ITPA genotype did not influence AZA dose, hematological parameters, or leucopenia risk. CONCLUSIONS: Our results suggest that routine genotyping of renal transplant recipients for TPMT variants may be useful in reducing the risk of AZA-related myelotoxicity, but there is not enough evidence to introduce ITPA testing into clinical practice.
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Authors: Dionna J Green; Son Q Duong; Gilbert J Burckart; Tristan Sissung; Douglas K Price; William D Figg; Maria M Brooks; Richard Chinnock; Charles Canter; Linda Addonizio; Daniel Bernstein; David C Naftel; Adriana Zeevi; James K Kirklin; Steven A Webber; Brian Feingold Journal: J Pediatr Pharmacol Ther Date: 2018 Mar-Apr