Factors associated with reduced infliximab exposure in the treatment of pediatric autoimmune disorders: a cross-sectional prospective convenience sampling study

Abstract

Background Inadequate systemic exposure to infliximab (IFX) is associated with treatment failure. This work evaluated factors associated with reduced IFX exposure in children with autoimmune disorders requiring IFX therapy. Methods In this single-center cross-sectional prospective study IFX trough concentrations and anti-drug antibodies (ADAs) were measured in serum from children diagnosed with inflammatory bowel disease (IBD) (n = 73), juvenile idiopathic arthritis (JIA) (n = 16), or uveitis (n = 8) receiving maintenance IFX infusions at an outpatient infusion clinic in a tertiary academic pediatric hospital. IFX concentrations in combination with population pharmacokinetic modeling were used to estimate IFX clearance. Patient demographic and clinical data were collected by chart review and evaluated for their relationship with IFX clearance. Results IFX trough concentrations ranged from 0 to > 40 μg/mL and were 3-fold lower in children with IBD compared to children with JIA (p = 0.0002) or uveitis (p = 0.001). Children with IBD were found to receive lower IFX doses with longer dosing intervals, resulting in dose intensities (mg/kg/day) that were 2-fold lower compared to children with JIA (p = 0.0002) or uveitis (p = 0.02). Use of population pharmacokinetic analysis to normalize for variation in dosing practices demonstrated that increased IFX clearance was associated with ADA positivity (p = 0.004), male gender (p = 0.02), elevated erythrocyte sedimentation rate (ESR) (p = 0.02), elevated c-reactive protein (CRP) (p = 0.001), reduced serum albumin concentrations (p = 0.0005), and increased disease activity in JIA (p = 0.009) and IBD (p ≤ 0.08). No significant relationship between diagnosis and underlying differences in IFX clearance was observed. Multivariable analysis by covariate population pharmacokinetic modeling confirmed increased IFX clearance to be associated with anti-IFX antibody positivity, increased ESR, and reduced serum albumin concentrations. Conclusions Enhanced IFX clearance is associated with immunogenicity and inflammatory burden across autoimmune disorders. Higher systemic IFX exposures observed in children with rheumatologic disorders are driven primarily by provider drug dose and interval selection, rather than differences in IFX pharmacokinetics across diagnoses. Despite maintenance IFX dosing at or above the standard recommended range for IBD (i.e., 5 mg/kg every 8 weeks), the dosing intensity used in the treatment of IBD is notably lower than dosing intensities used to treat JIA and uveitis, and may place some children with IBD at risk for suboptimal maintenance IFX exposures necessary for treatment response.

Potential Role of Methotrexate Polyglutamates in Therapeutic Drug Monitoring for Pediatric Inflammatory Bowel Disease

“…Children included in this secondary analysis completed a convenience-sampling cross-sectional investigation of IFX pharmacokinetics across different pediatric autoimmunity diagnoses [ 8 ]. Of the 21 children enrolled (median age 16 years (IQR 12, 17), 38% F, 90% Crohn’s disease), 10 had active disease (six mild, three moderate, and one severe) and 11 were in remission (Paris Disease Classification in Table 1 ).…”

Systemic exposure to hydroxychloroquine and its relationship with outcome in severely ill COVID‐19 patients in New York City

“…Indeed, this approach is quite normal and has been applied to many different studies. 15 , 16 , 17 , 18 , 19 Comparisons of our PK model with other models developed for HCQ is difficult, given the differences in sampling strategies, assays, incorporated metabolites, dose regimens, modelling and simulation software and strategies, and diseases and severity of disease between our study and those described in the literature. 13 , 20 , 21 , 22 , 23 However, corrected for the dose regimen, our serum concentration data were similar to earlier described plasma concentrations in COVID‐19 patients, which were in turn lower than those described in patients with malaria.…”

“…In the absence of such data, however, the validation of our model strongly suggests that the AUC is determined with acceptable accuracy and precision, regardless of the number of samples for each patient and regardless of the time these samples were collected. Indeed, this approach is quite normal and has been applied to many different studies 15–19 . Comparisons of our PK model with other models developed for HCQ is difficult, given the differences in sampling strategies, assays, incorporated metabolites, dose regimens, modelling and simulation software and strategies, and diseases and severity of disease between our study and those described in the literature 13,20–23 .…”

Population Pharmacokinetics of Infliximab in Children with Juvenile Idiopathic Arthritis

“…In addition to immunogenicity, a number of other patient factors are believed to influence IFX clearance and trough concentrations, including sex, age, presence of systemic inflammation, and serum albumin concentrations. 23,24 To date, little data are available for patients with JIA regarding a concentration-effect relationship of anti-TNF drugs, let alone on the optimal therapeutic drug ranges in children with JIA. PK in children differ from those in adults regarding distribution, metabolism, and clearance of therapeutic drugs.…”

“…In addition to immunogenicity, a number of other patient factors are believed to influence IFX clearance and trough concentrations, including sex, age, presence of systemic inflammation, and serum albumin concentrations. 23,24…”