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, [1.2-14.6]). Pretreatment predictors for subtherapeutic week 14 AUC included neutrophil CD64 > 6 (OR 4.5, [1.4-17.8]), ESR > 30 mm/h (OR 3.8, [1.4-11]), age < 10 years old (OR 4.2, [1.2-20]), and weight < 30 kg (OR 6.6, [2.1-25]). We created a decision-support 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.

Figure 1

Comparison of model accuracy between the (a) base pharmacokinetic (PK) model and the (b) full model that includes weight, serum albumin (ALB), neutrophil CD64 activity ratio (nCD64), antibody to infliximab (ATI), and erythrocyte sedimentation rate (ESR) as covariates of drug clearance. With the full model, the improved predicted accuracy is depicted as the observed drug concentrations (dots) and individual predicted curves (dashed-lines) are in closer proximity to the population predicted PK curve (solid line) when compared with the base model for each representative patient.^–

Figure 2

The predicted pharmacokinetic (PK) profile by the magnitude of each covariate with as-labeled (5 mg/kg) infliximab. The model default value for (a) ESR is 9 mm/h, (b) nCD64 is 4.6, (c) ATI is 22 ng/mL (undetectable level) and (d) ALB is 3.5 mg/dL. The respective colored line indicates the median PK profile for each covariate intensity, the shaded ribbon indicates the correspondent 5–95% prediction interval and the dashed horizontal line represents an infliximab concentration of 5 μg/mL. ALB, albumin; ATI, antibody to infliximab; ESR, and erythrocyte sedimentation rate; nCD64, neutrophil CD64.

Figure 3

Infliximab area under the curve (AUC) at (a) week 2 and (b) week 6 was compared for week 14 biochemical outcomes. (c) The week 14 AUC cutoff point associated with week 14 biochemical remission was determined with the Youden index from the receiver operating characteristic curve. Infliximab AUC at (d) week 14 (e) week 26, and (f) week 52 was compared for week 52 biochemical outcomes. AUROC, area under the receiver operating characteristic curve; CI, confidence interval; NPV, negative predictive value; PPV, positive predictive value; Sens., sensitivity; Spec., specificity.

Figure 4

Week 14 fecal calprotectin by quartiles and individual measures of infliximab pharmacokinetics including (a) total induction AUC, (b) week 14 C_trough, and (c) week 14 drug clearance. Post-tests to analyze between group comparisons were also performed for each measure with the associated Pvalues shown in each panel. AUC, area under the curve; C_trough, trough plasma concentration.

Figure 5

The infliximab pharmacokinetic (PK) dashboard is shown as a screen shot from the electronic health record. The patient’s previous infusion (a) intervals (weeks and days), (b) measured (actual) trough concentrations, (c) the model-predicted trough concentration from the last infusion, and (d) model-predicted trough concentrations and PK curves (blue dashed-line) for the next two infusions are shown. The dashboard is equipped with an adjustable target range (green-shaded) for trough concentrations and a display of previous laboratory results in the lower left panel. ALB, albumin; ESR, and erythrocyte sedimentation rate; nCD64, neutrophil CD64.