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The Effect of Polymorphisms and Other Biomarkers on Infliximab Exposure in Paediatric Inflammatory Bowel Disease: Development of a Population Pharmacokinetic Model

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Abstract

Background

Therapeutic drug monitoring (TDM) of infliximab has been shown to be a effective strategy for inflammatory bowel disease (IBD). Population pharmacokinetic (PopPK) modeling can predict trough concentrations for individualized dosing.

Objective

The aim of this study was to develop a PopPK model of infliximab in a paediatric population with IBD, assessing the effect of single nucleotide polymorphisms (SNPs) and other biomarkers on infliximab clearance.

Methods

This observational and ambispective single-centre study was conducted in paediatric patients with IBD treated with infliximab between July 2016 and July 2022 in the Paediatric Gastroenterology Service of the Hospital Universitari Vall d’Hebron (HUVH) (Spain). Demographic, clinical, and analytical variables were collected. Twenty SNPs potentially associated with variations in the response to infliximab plasma concentrations were analysed. infliximab serum concentrations and antibodies to infliximab (ATI) were determined by ELISA. PopPK modelling was performed using nonlinear mixed-effects analysis (NONMEM).

Results

Thirty patients (21 males) were included. The median age (range) at the start of infliximab treatment was 13 years (16 months to 16 years). A total of 190 samples were obtained for model development (49 [25.8%] during the induction phase). The pharmacokinetics (PK) of infliximab were described using a two-compartment model. Weight, erythrocyte sedimentation rate (ESR), faecal calprotectin (FC), and the SNP rs1048610 (ADAM17) showed statistical significance for clearance (CL), and albumin for inter-compartmental clearance (Q). Estimates of CL1 (genotype 1-AA), CL2 (genotype 2-AG), CL3 (genotype 3-GG), Q, Vc, and Vp (central and peripheral distribution volumes) were 0.0066 L/h/46.4 kg, 0.0055 L/h/46.4 kg, 0.0081 L/h/46.4 kg, 0.0029 L/h/46.4 kg, 0.6750 L/46.4 kg, and 1.19 L/46.4 kg, respectively. The interindividual variability (IIV) estimates for clearance, Vc, and Vp were 19.33, 16.42, and 36.02%, respectively.

Conclusions

A popPK model utilising weight, albumin, FC, ESR, and the SNP rs1048610 accurately predicted infliximab trough concentrations in children with IBD.

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Acknowledgements

This work has been carried out under the framework of the Gynecology, Obstetrics and Paediatrics doctoral program of the Autonomous University of Barcelona. We would like to thank the patients and their parents for their participation in the study. Also, thanks to Núria Padulles for her support at the beginning of the project, Maite Sanz for performing the infliximab and anti-infliximab antibody measurements, and Sonia García for helping with the prediction of concentrations and dose adjustment of infliximab in our patients.

Author information

Authors and Affiliations

  1. Pharmacy Department, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, 08035, Barcelona, Spain

    Susana Clemente-Bautista, Carlos J. Parramón-Teixidó, Maria J. Cabañas-Poy, Maria Q. Gorgas-Torner & Marta Miarons

  2. Department of Pharmaceutical Technology and Chemistry, Faculty of Pharmacy and Nutrition, University of Navarra, 31009, Navarra, Spain

    Iñaki F. Trocóniz

  3. Paediatric Gastroenterology and Clinical Nutrition Unit, Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, 08035, Barcelona, Spain

    Óscar Segarra-Cantón & Marina Álvarez-Beltrán

  4. Department of Paediatrics, Obstetrics and Gynaecology, Preventive Medicine and Public Health of the Universidad Autónoma de Barcelona, 08193, Bellaterra, Spain

    Óscar Segarra-Cantón

  5. Pharmacogenetics and Pharmacogenomics Laboratory, Pharmacy Department, Gregorio Marañón University Hospital, 28007, Madrid, Spain

    Sara Salvador-Marín & Luís A. López-Fernández

  6. Pharmacy and Pharmaceutical Technology and Physical Chemistry Department, University of Barcelona, 08028, Barcelona, Spain

    Helena Colom

  7. Pharmacy Department, Consorci Hospitalari de Vic, Vic, Barcelona, Spain

    Marta Miarons

Authors
  1. Susana Clemente-Bautista
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  2. Iñaki F. Trocóniz
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  3. Óscar Segarra-Cantón
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  4. Sara Salvador-Marín
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  6. Marina Álvarez-Beltrán
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Corresponding author

Correspondence to Susana Clemente-Bautista.

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Author Contributions

SCB and MMF conceived and designed the research; OSC and MAB had direct clinical responsibility for the patients; SCB and MMF participated in data acquisition and curation; IFT, SCB, and MMF performed the investigation; LAL-F and SS-M performed the genotyping; CJP performed the statistical analysis; SCB & MMF wrote the original draft; MJCP, OSC, MQGT, HCC, and IFT critically reviewed the scientific content of the manuscript; SCB and MMF obtained funds. All authors revised, read, and approved the final manuscript. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board statement

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Clinical Research Ethics Committee of Hospital Universitari Vall d’Hebron (protocol code SCB-INF-2020-01; date of approval 20/03/2020).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Funding Interests

This study was funded by a grant from the Sociedad Española de Farmacia Hospitalaria 2022 (SEFH).

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results.

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Clemente-Bautista, S., Trocóniz, I.F., Segarra-Cantón, Ó. et al. The Effect of Polymorphisms and Other Biomarkers on Infliximab Exposure in Paediatric Inflammatory Bowel Disease: Development of a Population Pharmacokinetic Model. Pediatr Drugs (2024). https://doi.org/10.1007/s40272-024-00621-1

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