Evaluation of pharmacokinetic metrics and pharmacodynamic biomarkers associated with endoscopic healing in pediatric Crohn's disease patients treated with anti-tumor necrosis factor biologics.
In a multicenter cross-sectional cohort of 87 anti-TNF-treated Crohn’s disease patients aged 1–22 years, lower CD64 biomarkers and slower infliximab clearance were associated with endoscopic healing, while anti-TNF trough concentrations were not.
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In a multicenter cross-sectional cohort of 87 anti-TNF-treated Crohn’s disease patients aged 1–22 years, lower CD64 biomarkers and slower infliximab clearance were associated with endoscopic healing, while anti-TNF trough concentrations were not.
Research significance
The study provides associative evidence that infliximab clearance and CD64-based pharmacodynamic biomarkers may distinguish patients with endoscopic healing; if prospectively validated, these measures could potentially guide anti-TNF dose escalation versus switching therapy, but no oncology application or clinical benefit from biomarker-guided treatment was tested.
Source abstract
BACKGROUND: Crohn's disease (CD) patients achieving deep remission, defined as clinical remission with endoscopic healing (EH), have a lower rate of CD-related adverse events. EH can be achieved with anti-tumor necrosis factor (TNF) dose optimizations directed by pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers. The primary aim was to identify PK metrics and PD biomarker cut-points associated with EH. METHODS: In this multicenter, cross-sectional study, we enrolled CD patients (age 1-22 years) who received an anti-TNF biologic (infliximab or adalimumab) for >6 months and underwent ileocolonoscopy. EH was defined as a simple endoscopic score-CD (SES-CD) < 3. RESULTS: Eighty-seven patients were enrolled with EH found in 55.2%. Lower levels of novel biomarkers neutrophil CD64, monocyte CD64, and soluble CD64 were associated with EH with cut-points of <4.5 ratio (AUROC 0.76), <44.6 ratio (AUROC 0.67), and <15.9 ng/mL (AUROC 0.67), respectively. There was no difference in the mean trough concentrations of infliximab or adalimumab between EH and non-EH, but the median infliximab clearance was higher in non-EH (0.26 L/day) compared to EH (0.21 L/day, P = .02). In our infliximab multivariable model, slower infliximab clearance, lower platelet count, and higher serum albumin were strong predictors for EH (AUC 0.90). CONCLUSIONS: We identified novel PK and PD cut-points for biomarkers associated with EH, including infliximab clearance and the novel CD64 biomarkers. Furthermore, we developed a multivariable PK and PD model for EH that, following validation, could guide dose escalation (PK failures) or prompt a switch to an alternate advanced therapeutic for PD failures.