VALIDATION OF AN INFLIXIMAB POPULATION PHARMACOKINETIC MODEL FOR MAINTENANCE DOSING IN PEDIATRIC PATIENTS WITH INFLAMMATORY BOWEL DISEASE
Authors: Singer Jason , Tong Dominic , Cumming Celine , Hughes Jasmine , Holmes Maya , Sferra Thomas , Moses Jonathan , Finkler Michael 
Published: January 2024

Abstract

INTRODUCTION
The use of infliximab has revolutionized the care of pediatric patients with inflammatory bowel disease (IBD); however, infliximab may lose efficacy over time during the maintenance phase and the use of therapeutic drug monitoring has been advocated to improve response rates. A population pharmacokinetic (popPK) model using infliximab concentrations, common clinical biomarkers, and demographic information to predict future infliximab concentrations would be clinically invaluable. Previous popPK models such as the Buurman [1] and Fasanmade [2] exist, but their utility, accuracy, and predictive values have not been clinically validated. This study aims to validate a reliable set of covariates for an infliximab popPK model that will predict maintenance drug concentrations and guide treatment decisions for children with IBD.

METHODS
This retrospective study included 134 pediatric patients with 503 infliximab trough concentrations between 5 and 21 years of age, seen at the Division of Pediatric Gastroenterology, Hepatology, and Nutrition at UH Rainbow Babies and Children’s Hospital between January 1, 2008 and December 31, 2018. We recorded the patients' therapeutic infliximab trough concentrations and other clinical and demographic factors. In previous work, we refit published popPK models using induction phase data. Here, we refit our originally constructed one-compartment model based on induction phase data, the Cleveland Model, with maintenance phase data to yield the Cleveland Refit model. We then tested six different models: Buurman (B), Buurman Refit (BR), Fasanmade (F), Fasanmade Refit (FR), Cleveland (C), and Cleveland Refit (CR). Each model was evaluated on root mean square error (RMSE), mean percent error (MPE), and accuracy of the predicted infliximab concentration. We defined accuracy as the percentage of samples each model correctly predicted to be on the same side of 5 ug/mL, which is our clinical trough target.

RESULTS
On the first infliximab concentration following the induction phase, published models refit on induction phase data (BR, FR) have higher accuracy but also higher RMSE than published models. In contrast, the CR model was refit on maintenance phase data and has higher accuracy (71.1% vs 66.7%) and lower RMSE (6.8 vs 7.8 ug/mL) and MPE (-5% vs 10%) than the previous induction-only model.

CONCLUSIONS
The CR model improved upon the performance of the induction-only models tested on this cohort. This study suggests refit popPK models on a specific patient population work well for predicting maintenance phase infliximab concentrations, and may be useful for personalization of dose of frequency for pediatric patients with IBD. Further validation with external data in a multicenter, prospective study is needed.
References
1) https://doi.org/10.1111/apt.13299
2) https://doi.org/10.1016/j.clinthera.2011.06.002