Qiaolin Zhao1,2, Myrthe Jongsma3, Stephanie Vuijk3, Brenda de Winter1,2, Tim Preijers1,2, Lissy de Ridder3
1Department of Hospital Pharmacy, Erasmus Medical Center, 2Rotterdam Clinical Pharmacometrics Group, 3Department of Paediatric Gastroenterology, Erasmus Medical Center/Sophia Children’s Hospital
Objectives Since the introduction of infliximab (IFX), multiple studies have suggested that pediatric inflammatory bowel disease (PIBD) patients have lower respond rates on weight-based dosing than adults, partially due to the differences found in the pharmacokinetics (PK) between pediatric and adults. Therefore, intensified IFX dosing regimens are required in pediatric patients to decrease the likelihood of poor response. However, dosing strategies for young PIBD (YPIBD) patients may be more intense than old PIBD (OPIBD) patients. One study demonstrated that PIBD patients of 7 years old or younger had reduced response rates to IFX and showed a lower likelihood of maintaining IFX therapy compared to older PIBD [1]. Another study indicated that approximately 72% of PIBD patients below 10 years old experience low trough levels, defined by a target concentration of 5.4 µg/mL, at start of maintenance (week 14) [2]. Therefore, YPIBD may require higher doses to attain similar target trough levels. Except for bodyweight, the continuously changing children’s body composition also affects the PK of IFX [2]. Although population PK (popPK) analyses allow to describe such physiological changes, no popPK analyses in YPIBD patients have yet been published in literature. For measuring IFX concentrations in serum, multiple Enzyme-Linked Immunosorbent Assay (ELISA) assays have been established and are applied for therapeutic drug monitoring (TDM). However, significant differences were observed between assay results, suggesting that therapeutic ranges for IFX may be assay-specific [3]. Similarly, another study highlighted significant discrepancies between assays in classifying IFX concentration ranges, emphasizing caution when comparing results and recommending the use of the same assay for longitudinal monitoring of IBD patients [4]. Moreover, pooled data may lead to varying PK parameter estimates. As the currently published popPK analyses for IFX only included data obtained from a single ELISA assay and pediatric patients above 10 years old, this study aimed to investigate the popPK of IFX in YPIBD patients (<10 years old) and to assess the effect of different IFX assays on the accuracy of PK parameter estimation. Methods Data from YPIBD patients were retrospectively collected in 14 European and Canadian centers. Pediatric patients treated with IFX between 2004 and 2016 were included and data was collected between 2015 and 2019. All children included in the study were less than 10 years of age at the initiation of IFX therapy. IFX concentrations were measured with different commercial ELISA kits. Evaluating the predictive performance of published popPK models was firstly carried out. If the published model were not sufficient, we would refine the model. Modeling re-building was initiated using the most parsimonious model with parameter initials taken from the best performing published model. Covariate analysis was performed and Monte Carlo simulations to investigate IFX assay impact and alternative dosing strategies were carried out when the model building was finished. Moreover, the infliximab PK parameters among YPIBD, old PIBD and adults were compared. External validation and model construction were performed in NONMEM version 7.4 and processing and visualization of data was performed in R 4.2.1. Results In total, 2150 IFX concentrations from 104 YPIBD patients were measured by six different IFX assays simultaneously. The median (range) age and bodyweight at start of IFX treatment of the population was 8.2 years old (1.2-10.0) and 25 kg (9.5-40.9), respectively. The external validation showed that the six selected published models were not sufficient to do the prediction in YPIBD data. Subsequently, a refined two-compartmental model was developed. For YPIBD patients, OPIBD patients and adults, the typical values (min-max) for clearance (CL) were 0.615-0.943 L/day/65kg, 0.015-0.353 L/day/65kg, and 0.317-0.350 L/day/65kg, respectively. Both albumin and C-reactive protein (CRP) allowed to explain the inter-individual variability obtained in CL. By applying stratification for the different IFX assays in the residual error model, prediction errors and CL estimates differed significantly between assays (P<0.05), while the estimated area under the curve for week 6–14 (AUCw6-14) remained similar (P>0.05) across all assays. With label-recommended dosing, IFX concentrations fell below target (5mg/L) for approximately 4 weeks in maintenance period after administration. Conclusions YPIBD patients demonstrated a higher IFX CL than older children and adults, with albumin and CRP identified as covariates relationships with CL. The differences obtained across the IFX assays did not affect overall drug exposure. To maintain trough levels above 5 mg/L in YPIBD patients, a dosing interval of 4 weeks is required.
[1] Kelsen JR, Grossman AB, Pauly-Hubbard H, Gupta K, Baldassano RN, Mamula P. Infliximab therapy in pediatric patients 7 years of age and younger. J Pediatr Gastroenterol Nutr. Dec 2014;59(6):758-62. [2] Jongsma MME, Winter DA, Huynh HQ, et al. Infliximab in young paediatric IBD patients: it is all about the dosing. Eur J Pediatr. Dec 2020;179(12):1935-1944. [3] Perry MH, McDonald TJ. Method Comparison Between ELISAs Suggests Therapeutic Ranges for Infliximab Should Be Assay-Specific. J Appl Lab Med. Nov 1 2018;3(3):515-517. [4] Bertin D, Serrero M, Grimaud JC, Desjeux A, Desplat-Jégo S. Monitoring of infliximab trough levels and anti-infliximab antibodies in inflammatory bowel diseases: A comparison of three commercially available ELISA kits. Cytokine. Feb 2020;126:154859.
Reference: PAGE 33 (2025) Abstr 11769 [www.page-meeting.org/?abstract=11769]
Poster: Drug/Disease Modelling - Other Topics