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Is It Useful to Monitor Thiopurine Metabolites in Pediatric Patients with Crohn’s Disease on Combination Therapy? A Multicenter Prospective Observational Study

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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 × 108 erythrocytes (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.

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Author information

Authors and Affiliations

  1. Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, V Uvalu 84, 150 06, Prague 5, Czech Republic

    Kristyna Pospisilova, Ondrej Hradsky, Tereza Lerchova, Kristyna Zarubova, Ivana Copova, Lucie Gonsorcikova & Jiri Bronsky

  2. Laboratory of Growth Regulators, Palacky University Olomouc and Institute of Experimental Botany AS CR, Slechtitelu 27, 783 71, Olomouc, Czech Republic

    Jitka Siroka & Lubor Urbanek

  3. Department of Pediatrics, Faculty of Medicine and Dentistry, Palacky University and University Hospital, I.P. Pavlova 185/6, 779 00, Olomouc, Czech Republic

    Eva Karaskova, Maria Velganova-Veghova, Milos Geryk & Vladimir Mihal

  4. Institute 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

    Irena Francova

Authors
  1. Kristyna Pospisilova
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  2. Jitka Siroka
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  9. Maria Velganova-Veghova
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  13. Vladimir Mihal
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Corresponding author

Correspondence to Kristyna Pospisilova.

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Funding

This work was supported by Ministry of Health (Czech Republic) funding for the conceptual development of research organizations [00064203, University Hospital Motol, Prague, Czech Republic, and 0098892, University Hospital, Olomouc, Czech Republic], and the OP VVV ENOCH [CZ.02.1.01/0.0/0.0/16_019/0000868].

Disclosure of potential conflicts of interest

Pospisilova K: lectures/congress fees/consultancy (outside submitted work)—MSD, Nutricia, Nestlé and Mead Johnsons; Karaskova E: lectures/congress fees/consultancy (outside submitted work)—MSD, AbbVie, Nutricia, and Nestlé; Hradsky O: lectures/congress fees/consultancy (outside submitted work)—MSD, AbbVie, Nutricia, Nestlé, Ferring, and Falk; Lerchova T: lectures/congress fees/consultancy (outside submitted work)—Nutricia, Ferring and Biocodex; Zarubova K: lectures/congress fees/consultancy (outside submitted work)—Nutricia and Nestlé; Velganova-Veghova M: congress fees/consultancy (outside submitted work)—MSD, AbbVie, Nutricia, and Nestlé; Bronsky J: lectures/congress fees/consultancy (outside submitted work)—MSD, AbbVie, Nutricia, Nestlé, Ferring, Biocodex, and Walmark; Gonsorcikova L, Francova I, Geryk M, Copova I, Mihal V, Siroka J, and Urbanek L report no conflicts of interest.

Ethics approval

The protocol for the observational study was approved by the Ethics Committees of the University Hospital Motol and the 2nd Medical Faculty of Charles University in Prague.

Informed consent

Written informed consent was obtained from legal guardians before study enrollment.

Consent for publication

Non applicable.

Study registration

The study has been registered retrospectively in the ENCePP registry (encepp.eu), it can be found under the registration number EUPAS38918. Registered on 12 January 2021.

Data availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

The code is available from the corresponding author on reasonable request.

Author contributions

PK: study design, literature search, data collection, patient recruitment, thiopurine metabolite measurement, data analysis, manuscript writing; SJ: data collection, thiopurine metabolite measurement and laboratory supervision, manuscript critical revision; KE: data collection, patient recruitment, manuscript critical revision; HO: study design, data analysis and interpretation, manuscript critical revision; LT: study design, data collection, patient recruitment, manuscript critical revision, ZK: data collection, patient recruitment, manuscript critical revision; CI: data collection, patient recruitment, manuscript critical revision; GL: data collection, patient recruitment, manuscript critical revision; V-VM: data collection, patient recruitment, manuscript critical revision; FI: data collection, infliximab levels and antibodies measurement supervision, manuscript critical revision; UL: thiopurine metabolite measurement—method optimization, data collection, manuscript critical revision; GM: data collection, patient recruitment, manuscript critical revision; Mihal V: data collection, supervision, manuscript critical revision; BJ: study design and supervision, literature search, manuscript writing. All authors read and approved the final manuscript.

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Pospisilova, K., Siroka, J., Karaskova, E. et al. Is It Useful to Monitor Thiopurine Metabolites in Pediatric Patients with Crohn’s Disease on Combination Therapy? A Multicenter Prospective Observational Study. Pediatr Drugs 23, 183–194 (2021). https://doi.org/10.1007/s40272-021-00439-1

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