The effect of aging on infliximab exposure and response in patients with inflammatory bowel diseases

Abstract

Aims Controversies regarding infliximab treatment in elderly patients with inflammatory bowel diseases remain. We evaluated the effect of patient's age on infliximab exposure, efficacy and safety. Methods Retrospective case‐control data of patients receiving infliximab induction treatment were analysed. A population pharmacokinetic model was developed to estimate individual pharmacokinetic parameters. A logistic regression model was used to investigate the effect of exposure on endoscopic remission. Repeated time‐to‐event models were developed to describe the hazard of safety events over time. Results A total of 104 patients (46 elderly, ≥65 years) were included. A two‐compartment population pharmacokinetic model with linear elimination adequately described the data. Infliximab clearance decreased with older age, higher serum albumin, lower fat‐free mass, lower C‐reactive protein and absence of immunogenicity. Yet, infliximab exposure was not significantly different between elderly and nonelderly. Regardless of age, an infliximab trough concentration at week (w)14 of 15.6 mg/L was associated with a 50% probability of attaining endoscopic remission between w6 and w22. Infliximab exposure during induction treatment was not a risk factor of (severe) adverse events. The hazard of severe adverse events and malignancy increased by 2% and 7%, respectively, with increasing year of age. Concomitant immunomodulator use increased the hazard of infection by 958%, regardless of age. Conclusions Elderly patients attained infliximab exposure and endoscopic remission similarly to nonelderly patients. Therefore, the same infliximab trough concentration target can be used in therapeutic drug monitoring. The hazards of severe adverse events and malignancy increased with age, but not with infliximab exposure.

Application of a Precision‐Dosing Model to a Real‐World Cohort of Patients on Infliximab Maintenance Therapy: Drug Usage and Cost Analysis

“…Our univariate analysis showed increasing age as a predictor of subtherapeutic infliximab levels. This contrasts with other studies showing increasing age reduces infliximab clearance 21 ; thus, it is not surprising that age was not an independent predictor of subtherapeutic infliximab drug levels on multivariate analysis. The multivariate analysis identified a lower infliximab trough concentration prior to dose X being significantly associated with a subtherapeutic infliximab dose X, defined by subsequent subtherapeutic infliximab trough concentrations as determined by iDOSE.…”

External Model Performance Evaluation of Twelve Infliximab Population Pharmacokinetic Models in Patients with Inflammatory Bowel Disease

“…All three models based on ADA measurements by HMSA were included in the analysis and are, hereafter, referred to as I (ADA covariate on the patient level), II (ADA covariate on sample level), and III (ADA concentrations as a continuous covariate). Eleven out of 25 models (Ternant et al, 2008 [ 44 ], Dotan et al, 2014 [ 45 ], Ternant et al, 2015 [ 46 ], Brandse et al, 2017 [ 47 ], Kevans et al, 2018 [ 48 ], Dreesen et al, 2019 [ 49 ], Matsuoka et al, 2019 [ 50 ], Petitcollin et al, 2019 [ 51 ], Dreesen et al, 2020 [ 27 ], Bauman et al, 2020 [ 21 ], and Kantasiripitak et al, 2021 [ 26 ]) could not be evaluated because of data set incompatibility (e.g., missing covariates in our data set) or lack of reported model implementation details. The model by Grišić et al was not included in the analysis as it was specifically focused on modeling the effects of pregnancy affecting infliximab PK [ 52 ].…”

“…As infliximab trough concentrations exhibit high inter-individual variability and, hence, contribute to a high rate of primary and secondary non-response [ 9 , 12 , 13 , 14 , 18 ] and as infliximab drug exposure is a predictor of clinical response [ 6 , 10 , 11 , 12 ], dose selection for infliximab could benefit considerably from population pharmacokinetic modeling and MIPD [ 31 , 63 ]. Consequently, many efforts have been made to analyze infliximab PK, quantifying and explaining inter-individual variability in various population pharmacokinetic models [ 21 , 23 , 24 , 25 , 26 , 27 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ].…”

“…A good understanding of the high variability in infliximab trough levels is essential for dose individualization strategies [ 4 , 19 , 20 , 21 , 22 ]. In the past, several efforts have been made to characterize infliximab pharmacokinetics (PK), including the quantification and explanation of inter-individual variability, and to develop population pharmacokinetic models for dose individualization [ 21 , 23 , 24 , 25 , 26 , 27 ]. While these analyses identified various covariates (e.g., albumin levels, sex, weight, ADA development, and use of concomitant immunomodulators) that influence infliximab CL and volume of distribution (V d ), the covariates could only partly explain the observed inter-individual and inter-occasion variability (IOV) [ 23 , 24 , 26 , 27 ].…”

Model-Informed Precision Dosing during Infliximab Induction Therapy Reduces Variability in Exposure and Endoscopic Improvement between Patients with Ulcerative Colitis

“…The 10 mg/kg dosing may result in very high exposures, which were predicted in the present study to be beneficial to patients. In reality, these highly exposed patients may present with adverse drug reactions such as infections, especially in the elderly, and MIPD may benefit these patients by reducing toxicity [ 27 , 28 , 29 ].…”