Paediatr Drugs. 2021 Mar;23(2):183-194.doi: 10.1007/s40272-021-00439-1. Epub 2021 Mar 11.

Kristyna Pospisilova ¹, Jitka Siroka ², Eva Karaskova ³, Ondrej Hradsky ⁴, Tereza Lerchova ⁴, Kristyna Zarubova ⁴, Ivana Copova ⁴, Lucie Gonsorcikova ⁴, Maria Velganova-Veghova ³, Irena Francova ⁵, Lubor Urbanek ², Milos Geryk ³, Vladimir Mihal ³, Jiri Bronsky ⁴

Author information

• ¹Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, V Uvalu 84, 150 06, Prague 5, Czech Republic. potuznikovakris@gmail.com.
• ²Laboratory of Growth Regulators, Palacky University Olomouc and Institute of Experimental Botany AS CR, Slechtitelu 27, 783 71, Olomouc, Czech Republic.
• ³Department of Pediatrics, Faculty of Medicine and Dentistry, Palacky University and University Hospital, I.P. Pavlova 185/6, 779 00, Olomouc, Czech Republic.
• ⁴Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, V Uvalu 84, 150 06, Prague 5, Czech Republic.
• ⁵Institute of Medical Biochemistry and Laboratory Diagnosis, General University Hospital and 1st Faculty of Medicine, Charles University in Prague, Na Bojisti 3, Prague 2, 121 08, Prague, Czech Republic.

Abstract

Background: The additional value of azathioprine concomitant treatment on infliximab pharmacokinetics in children is not well described yet.

Aims: In the present study, we aimed to describe the relationship between thiopurine metabolite levels, infliximab trough levels, anti-IFX antibody formation, and clinical and laboratory markers of disease activity in pediatric patients with Crohn's disease, and to assess non-adherence.

Methods: Data were collected prospectively during repeated visits from pediatric patients followed for Crohn's disease in two Czech pediatric inflammatory bowel disease centers between January 2016 and June 2017. Thiopurine metabolites (6-thioguanine and 6-methylmercaptopurine) were measured by high-performance liquid chromatography. Infliximab trough levels and anti-IFX antibody serum levels were measured routinely by ELISA. The risk of loss of response to infliximab therapy was also assessed.

Results: A significant association between infliximab serum levels and 6-thioguanine erythrocyte levels was observed when tested as categorical variables (63 patients, 321 observations). To predict infliximab levels > 5 µg/mL, we propose a 6-thioguanine cutoff of 278 pmol/8 × 10⁸erythrocytes (sensitivity, 0.799; specificity, 0.347). A higher loss-of-response-to-infliximab rate (tested in a subgroup of 51 patients) was observed in patients with undetectable 6-thioguanine levels than in those with detectable levels (p = 0.026). Non-adherence to azathioprine therapy was suspected in 20% of patients.

Conclusion: Thiopurine metabolite monitoring in pediatric patients with Crohn's disease is useful when optimizing combination therapy. Pediatric patients with undetectable 6-thioguanine levels are more likely to lose response to infliximab therapy. When targeting optimal infliximab levels, the 6-thioguanine cutoff levels in children appear to be higher than in adults.