A Model-Based Tool for Guiding Infliximab Induction Dosing to Maximize Long-term Deep Remission in Children with Inflammatory Bowel Diseases

Abstract

Background and aims Adequate infliximab concentrations during induction treatment are predictive for deep remission (corticosteroid-free clinical and endoscopic remission) at six months in children with inflammatory bowel diseases (IBD). Under standard infliximab induction dosing, children often have low infliximab trough concentrations. Model-informed precision dosing (MIPD) (i.e., model-based therapeutic drug monitoring) is advocated as a promising infliximab dosing strategy. We aimed to develop and validate an MIPD framework for guiding paediatric infliximab induction treatment. Methods Data from 31 children with IBD (4-18years) receiving standard infliximab induction dosing (5mg/kg at week [w]0, w2, and w6) were repurposed. Eight paediatric population pharmacokinetic models were evaluated. Modelling and simulation were used to identify exposure targets, an optimal sampling strategy, and develop a multi-model prediction algorithm for implementation into an MIPD software tool. A role for infliximab clearance monitoring was evaluated. Results A 7.5mg/L infliximab concentration target at w12 was associated with 64% probability of deep remission at six months. With standard dosing, less than 80% of simulated children <40kg attained this target. The w12 target was most accurately and precisely achieved by implementing MIPD at w6 using the w6 infliximab concentration (rapid assay required). The multi-model algorithm outperformed single models when optimising the w6 dose based on both w2 and w4 concentrations. MIPD using only the w2 concentration resulted in biased and imprecise predictions. Infliximab clearances at w6 and w12 were predictive for deep remission. Conclusions A freely available, multi-model MIPD tool facilitates infliximab induction dosing and improves deep remission rates in children with IBD.

Early infliximab trough levels in paediatric IBD patients predict sustained remission

“…before the third infusion), an infliximab concentration between 8.3 and 13.5 mg/L predicts clinical remission in the early postinduction phase. 13 , 14 , 21 An infliximab concentration higher than 5–7 mg/L measured at week 14 (i.e. before the fourth infusion) not only predicts short-term biochemical or endoscopic remission but also a sustained effect that lasts until week 52.…”

Best Practice for Therapeutic Drug Monitoring of Infliximab: Position Statement from the International Association of Therapeutic Drug Monitoring and Clinical Toxicology

“…70 Similarly, a recent study involving children with IBD receiving standard infliximab induction dosing revealed that infliximab clearance at weeks 6 and 12 was predictive of deep remission. 71 An RCT from South Korea, encompassing 112 biologic-naive children with CD who responded to induction treatment with infliximab, demonstrated the superiority of proactive TDM over clinically based dosing in sustained corticosteroid-free clinical remission and endoscopic healing. 72 A retrospective single-center study assessing outcomes in pediatric patients receiving either infliximab or adalimumab before (pre-TDM; 72.2% received infliximab) and after the implementation of institutional guidelines for proactive TDM (post-TDM; 65.5% received infliximab) found that proactive TDM improved key clinical outcomes, including sustained clinical remission, the incidence of high ATI titer, and anti-TNF cessation related to ATI.…”

“…Moreover, the predictive performance of both single- and multi-model approaches remained robust even in the absence of covariate data, as long as a single most recent TC (preferably at the point of care) of infliximab was provided. Kantasiripitak et al 71 also expanded their work to pediatric patients with IBD.…”

TDM of belatacept and other biologicals in transplantation.

“…However, the implementation of such tools into the clinical use of biologicals has been limited, which may also reflect the sparse evidence for the role of TDM in this setting. There are examples especially in the therapy of inflammatory bowel disease and some other immune diseases where MIPD has been explored to guide personalization [20][21][22][23]. Also for a drug like alemtuzumab a PK/PD model was developed for patients treated for chronic lymphocytic leukaemia (CLL) [24].…”