Real‐World Infliximab Pharmacokinetic Study Informs an Electronic Health Record‐Embedded Dashboard to Guide Precision Dosing in Children with Crohn’s Disease

Abstract

Standard-of-care infliximab dosing regimens were developed prior to the routine use of therapeutic drug monitoring and identification of target concentrations. Not surprisingly, subtherapeutic infliximab concentrations in pediatric Crohn's disease (CD) are common. The primary aim was to conduct a real-world pharmacokinetic (PK) evaluation to discover blood biomarkers of rapid clearance, identify exposure targets, and a secondary aim to translate PK modeling to the clinic. In a multicenter observational study, 671 peak and trough infliximab concentrations from 78 patients with CD were analyzed with a drug-tolerant assay (Esoterix; LabCorp, Calabasas, CA). Individual area under the curve (AUC) estimates were generated as a measure of drug exposure over time. Population PK modeling (nonlinear mixed-effect modeling) identified serum albumin, antibody to infliximab, erythrocyte sedimentation rate (ESR), and neutrophil CD64 as biomarkers for drug clearance. Week 14 and week 52 biochemical remitters (fecal calprotectin < 250 µg/g) had higher infliximab exposure (AUC) throughout induction. The optimal infliximab AUC target during induction for week 14 biochemical remission was 79,348 µg*h/mL (area under the receiver operating characteristic curve (AUROC) 0.77, [0.63-0.90], 85.7% sensitive, and 64.3% specific) with those exceeding the AUC target more likely to achieve a surgery-free week 52 biochemical remission (OR 4.3,). Pretreatment predictors for subtherapeutic week 14 AUC included neutrophil CD64 > 6 (OR 4.5,), ESR > 30 mm/h (OR 3.8,), age < 10 years old (OR 4.2,), and weight < 30 kg (OR 6.6,). We created a decisionsupport PK dashboard with an iterative process and embedded the modeling program within the electronic health record. Model-informed precision dosing guided by real-world PKs is now available at the bedside in real-time.

A population physiologically‐based pharmacokinetic model to characterize antibody disposition in pediatrics and evaluation of the model using infliximab

“…While we did not include between-subject variability in our model, since most patients in the two cohorts had two or fewer measurements, it has been reported that incorporating the time-varying covariates in the model may improve between-subject variability. 65 was similar to the clearance in adult patients with RA, 39,67-69 and agreed with statements that clearance of most mAbs were comparable between adults and paediatrics after adjusting for body size. 70,71 However, our finding contradicted some review articles which concluded that most mAbs show a higher BW-normalized clearance in paediatrics than in adults.…”

“…63 The estimated residual variability (32.3%) in our study was within the range of the reported values for IFX PK models in paediatrics. 31,65 The between-subject variability and assay error may contribute to this uncertainty. The assays used to analyse IFX concentrations in our study have reported variability of 20% for cohort 1 66 and cohort 2, 27 which can contribute to the observed residual variability.…”

“…In addition, our PBPK model predicts that the weightnormalized clearance is relative consistent across different paediatric ages, which may seem to contradict some studies that use a population PK model approach and conclude a nonlinear relationship between weight and IFX clearance. 23,31,34,65 However, one should be cautious when directly comparing the estimated parameters (i.e., clearance, volume of distribution) between PBPK modelling and population PK modelling approaches, since both systems have their unique features and emphases. For example, the PBPK models consider the BW-related changes in organ weights and flow rates, where the physiology and autonomy parameterization have been incorporated.…”

Eculizumab precision-dosing algorithm for thrombotic microangiopathy in children and young adults undergoing HSCT

“…The lower albumin levels in bleeding patients could be partly involved in the high clearance as reported for other monoclonal antibodies (mAbs) such as infliximab and anti-PD-L1 antibody. [29][30][31][32] In fact, our study showed that the baseline albumin levels in bleeding patients were significantly lower than in non-bleeding patients. However, the low albumin may cause increased protein turnover, resulting in facilitating degradation of IgG, including mAb, and an increase in mAb neonatal Fc receptor-mediated clearance.…”

Infliximab Efficacy May Be Linked to Full TNF-α Blockade in Peripheral Compartment—A Double Central-Peripheral Target-Mediated Drug Disposition (TMDD) Model

“…Infliximab pharmacokinetics was analyzed using compartmental modeling in more than 30 studies to date. Some of these studies reported predictive models suitable for model-based therapeutic drug monitoring of infliximab [2][3][4]. The aim of individual dosing regimen to maintain serum trough concentrations of infliximab above target concentrations associated with good clinical response.…”