Journal of Pharmacovigilance

Abstract

Thiopurine S-Methyltransferase Phenotype and Genotype in Pediatric Patients with Inflammatory Bowel Disease; Implication for Azathioprine Treatment

Maciej Jankowski, Piotr Landowski, Robert Kowalski, Ewelina Kreft, Irena Audzeyenka, Malgorzata Kasztan, Barbara Kaminska and Miroslawa Szczepanska-Konkel

Inflammatory Bowel Disease (IBD) is more prevalent in children than adults, and the incidence is increasing. IBD is treated with thiopurines, metabolized by thiopurine S-methyltransferase (TPMT) and inter-individual variability in activity of TPMT affecting therapy efficiency and drug toxicity arises from genetic polymorphisms, mainly TPMT*2, *3A, and *3C. The aim was to investigate the frequency distribution of TPMT activity, determine the penetration rate of TPMT*2, *3A, and *3C alleles in children, and compare TPMT activity in children and adults with IBD. The study included 85 children, 45% with Crohn’s disease (CD) and 55% with ulcerative colitis (UC), and 31 adults with IBD. TPMT activity was measured with radiochemistry. TPMT*2, *3A, and *3C alleles were investigated with PCR and restriction fragment length polymorphism analyses. Children showed median TPMT activities of 13.12 and 13.19 U/ml RBC in CD and UC, respectively, with 4.8-fold variability (range, 4.74 - 22.56 U/ml RBC). TPMT activity was similar in children and adults; ranges: 5.56-21.34 vs. 9.61-17.84 U/ml RBC, respectively, in CD; and 4.74-22.56 vs. 5.19-21.98 U/ml RBC, respectively, in UC. Patients with CD and UC treated with azathioprine displayed similar TPMT activities, similar adverse event frequencies, and similar numbers of non-responders. One out of 85 patients (1.18%) was heterozygous with TPMT*1/TPMT*2 (TPMT activity: 5.19 ± 0.05 U/ml RBC). Individuals with low-intermediate TPMT activity (<8 U/ ml RBC) did not carry mutant alleles *3A or *3C. TPMT phenotypes were similar in children and adults with inflammatory bowel disease.