Q. Zhao (1,2), M.M.E Jongsma (3), S.A. Vuijk (3), B.C.M. de Winter (1,2), T.Preijers (1,2), L. de Ridder (3)
(1) Department of pharmacy, Erasmus MC, Rotterdam, the Netherlands, (2) Rotterdam Clinical Pharmacometrics Group, (3) Department of Paediatric Gastroenterology, Erasmus Medical Center/Sophia Children’s Hospital, Rotterdam, the Netherlands
Objectives:
Inflammatory bowel disease (IBD) represents chronic inflammatory disorders affecting the gastrointestinal tract, including Crohn’s disease (CD) and ulcerative colitis (UC). These disorders result from a dysregulated mucosal immune response to intestinal microflora. They are influenced by various extrinsic and intrinsic factors, such as alterations in gut microbes, immune responses, genetic susceptibility, and environmental influences. Infliximab (IFX), a chimeric mouse-human monoclonal antibody, is engineered by integrating the murine-variable region into the human constant region. This antibody effectively binds to and neutralizes TNF-a, thereby mitigating inflammatory symptoms and demonstrating efficacy in the treatment of IBD. Despite the success of infliximab, some studies [1-3] have reported suboptimal exposure and low trough levels in IBD patients, particularly among children. One study[4] indicated that approximately 72% of pediatric IBD patients below 10 years old experience low trough levels, defined by a target concentration of 5.4 μg/mL, at the start of maintenance (week 14). Low trough levels are often associated with diminished clinical and endoscopic remission rates, heightened immunogenicity, and an increased risk of developing a complicated disease course. Our study aims to investigate the pharmacokinetics of IFX in pediatric patients, identifying potential influential covariates and laying the groundwork for the development of a dashboard tool for IFX therapeutic drug monitoring.
Methods:
IFX therapeutic drug monitoring data from young children were retrospectively collected in 14 European and Canadian centers. Children treated with IFX between 2004-2016 were included and data was collected between 2015 and 2019. Non-linear mixed-effects modeling was used to develop a population pharmacokinetic model and perform a covariate analysis using NONMEM 7.4 (ICON Development Solutions, Ellicott City, MD, USA). Goodness of fit (GOF) plots and visual predictive check (VPC) plots were used to evaluate the model and a bootstrap analysis was applied to check the robustness of the final model.
Results:
From 104 young pediatric IBD patients, 2150 infliximab concentrations were obtained. The median age was 9.0 years-old (ranging from 1.2 to14.8 years old), median body weight was 27.2kg (ranging from 9.5~74.9 kg), absence of anti-drug-antibodies to infliximab (ATI) was 67.3%, whereas presence was 32.7%. A one-compartment model with power estimated allometric scaling best described IFX in IBD patients. Given that 12% of the observations was below the lower limit of quantification (LLOQ), the M3 method was performed. Population PK parameters included clearance (CL) (1.54 L/day/70kg), volume of distribution (V) (90.4 L/70kg), whereas the residual unexplained variability was 69.3% (%CV). Power of allometric scaling on CL was 1.34 and 2.23 on V. Inter-individual variability (IIV) was only obtained for CL. ATI was included as a categorical covariate relationship on CL (ΔOFV=27.6), which resulted in a decrease of IIV for CL from 48.3% to 46.9%. Resulting from the covariate analysis, ATI positive patients have a 1.35-fold higher CL than ATI negative patients. GOF plots and VPCs revealed a strong concordance between the observed and predicted IFX concentrations. The bootstrap 95% confidence intervals demonstrated reasonably good precision for all the parameters.
Conclusions:
This study provided the first population PK description of IFX in very young pediatric IBD patients. A correlation between body weight and clearance was found. Moreover, ATI positive patients have higher CL than ATI negative patients from this young population. These relationships should be taken into account when dosing IFX.
References:
[1] Chung A, Carroll M, Almeida P, Petrova A, Isaac D, Mould D, Wine E, Huynh H. Early Infliximab Clearance Predicts Remission in Children with Crohn’s Disease. Dig Dis Sci. 2023 May;68(5):1995-2005.
[2] Chang HP, Shakhnovich V, Frymoyer A, Funk RS, Becker ML, Park KT, Shah DK. A population physiologically-based pharmacokinetic model to characterize antibody disposition in pediatrics and evaluation of the model using infliximab. Br J Clin Pharmacol. 2022 Jan;88(1):290-302.
[3] Frymoyer A, Piester TL, Park KT. Infliximab Dosing Strategies and Predicted Trough Exposure in Children With Crohn Disease. J Pediatr Gastroenterol Nutr. 2016 May;62(5):723-7. Frymoyer A, Piester TL, Park KT. Infliximab Dosing Strategies and Predicted Trough Exposure in Children With Crohn Disease. J Pediatr Gastroenterol Nutr. 2016 May;62(5):723-7.
[4] Jongsma MME, Winter DA, Huynh HQ, Norsa L, Hussey S, Kolho KL, Bronsky J, Assa A, Cohen S, Lev-Tzion R, Van Biervliet S, Rizopoulos D, de Meij TGJ, Shouval DS, Wine E, Wolters VM, Martinez-Vinson C, de Ridder L; Paediatric IBD Porto Group of ESPGHAN. Infliximab in young paediatric IBD patients: it is all about the dosing. Eur J Pediatr. 2020 Dec;179(12):1935-1944.
Reference: PAGE 32 (2024) Abstr 10959 [www.page-meeting.org/?abstract=10959]
Poster: Drug/Disease Modelling - Paediatrics