Infliximab Dosing Strategies and Predicted Trough Exposure in Children With Crohn Disease

Abstract

Objectives Standard infliximab maintenance dosing of 5 mg/kg every 8 weeks may be inadequate to consistently achieve sufficient drug exposure to minimize loss of response or treatment failure in pediatric Crohn’s disease (CD). We aimed to determine the predicted infliximab trough concentrations in children with CD during maintenance therapy and the percentage of patients achieving target trough concentration >3 μg/ml. Methods A Monte Carlo simulation analysis was constructed using a published population pharmacokinetic model based on data from 112 children in the REACH trial. We assessed maintenance dosing strategies of 5, 7.5, and 10 mg/kg at dosing intervals of every 4, 6, and 8 weeks for children that differed by age, weight, albumin level, and concomitant immunomodulator therapy. Results Based on the index case of a 10 year old with CD receiving standard infliximab dosing with concomitant immunomodulator therapy, the median (IQR) simulated infliximab trough concentration at week 14 was 1.3 (0.5–2.7) μg/ml, and 2.4 (1.0–4.8) μg/ml for albumin levels of 3 and 4 g/dl, respectively. Among 1000 simulated children in the model, trough concentration >3 μg/ml at week 14 was achieved 21% and 41% of the time for albumin levels of 3 and 4 g/dl, respectively. Conclusions Standard infliximab maintenance dosing in children with CD is predicted to frequently result in inadequate exposure, especially when albumin levels are low. Optimized dosing strategies for individual patients are needed to achieve sufficient drug exposure during infliximab maintenance therapy.

Infliximab and its biosimilar produced similar first‐year therapy outcomes in patients with inflammatory bowel disease

“…The trough levels during induction were higher during 2016, and it is very likely that this reflects a change in clinical practice during this period, as studies carried out around this time reported better responses in young children with higher doses. 16,17 Disappointingly, although the trough levels during induction were higher, we did not observe any increase in the proportion of patients that maintained their therapeutic response. There were no major adverse events during the study period, no alarming signs and no acute infusion reactions with either of these drugs.…”

Application of Population Pharmacokinetic Modeling for Individualized Infliximab Dosing Strategies in Crohn Disease

“…The pharmacokinetics of infliximab are highly variable in this population and consequently dose requirements will vary between patients. (3,11) In the cohort of children examined in the current study, the predicted infliximab maintenance dosing strategy needed to achieve a trough concentration >3 μg/ml was quite heterogeneous and ranged from the standard dosing of 5 mg/kg every 8 weeks up to 5 mg/kg every 4 weeks (Figure 3A). Our cohort was homogenous in terms of serum albumin (only 1 patient had a serum albumin < 3.5), and serum albumin is the most influential predictor of infliximab clearance and trough achievement.…”

“…Our cohort was homogenous in terms of serum albumin (only 1 patient had a serum albumin < 3.5), and serum albumin is the most influential predictor of infliximab clearance and trough achievement. (11) Even greater heterogeneity in dose needs will likely be present in a larger, more diverse population. In addition, we demonstrated the potential challenges of achieving trough concentrations >3 μg/ml with even the most aggressive dosing (i.e.…”

“…(11) Higher infliximab doses and/or shorter dosing intervals were predicted to be needed to consistently achieve a trough concentration >3 μg/ml during maintenance dosing. Similarly, a prospective observational study found that 44% (n=10/23) of children with Crohn's disease had a trough concentration <3 μg/ml when receiving standard infliximab maintenance dosing of 5 mg/kg every 8 weeks.…”

Targeted Dosing as a Precision Health Approach to Pharmacotherapy in Children with Inflammatory Bowel Disease

“…For example, reliance on adult dosing in children with Crohn's disease can lead to less than 41% probability of adequate drug exposure. 24 Such significant discrepancies in drug clearance profiles between children and adults can result in early drug failure and worse outcomes for children with IBD. 24 Choosing the correct pharmacotherapy and targeting pharmacotherapy in an evidencebased way is critical to ensuring appropriate patient care aimed at optimizing future health gains.…”