Clinical pharmacokinetics · 2026
Pharmacometric Targets During Anti-TNF Induction and Their Association with Deep Remission in Pediatric Crohn's Disease.
СтатьяМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Nasr Alexander, Mizuno Tomoyuki, Irie Kei, Dillman Jonathan R, Jackson Kimberly, Lynch Kimberly, Horrell Alexa, Aviles Thomas, Chun Kelly, Yang Jane, Boyle Brendan, Hyams Jeffrey S, Noe Joshua, Denson Lee A, Minar Phillip
Аннотация
BACKGROUND AND OBJECTIVE: Personalizing anti-tumor necrosis factor (TNF) therapy in pediatric Crohn's disease (CD) remains challenging due to variable drug clearance and response. Identifying pharmacokinetic (PK) and pharmacodynamic (PD) predictors of deep remission could enable precision dosing strategies. The primary aim was to define PK metrics and PD biomarkers associated with deep remission.
METHODS: Patients initiating infliximab or adalimumab were prospectively enrolled from four pediatric centers with longitudinal blood and stool biospecimens collected for one year. Deep remission was defined as a combination of weighted pediatric CD activity index (wPCDAI) < 12.5 and Simple Endoscopic Score-CD < 3. Trough concentrations (cTrough) were measured throughout the study. Drug exposure (area under the curve, AUC) and clearance were estimated using drug-specific population PK models and Bayesian estimation using nonlinear mixed-effects modeling (NONMEM).
RESULTS: Deep remission was achieved in 34/70 (48.6%) with no difference in outcomes between biologics. Infliximab cTrough thresholds associated with deep remission were 33 µg/mL (Week 2), 15 µg/mL (Week 6), and 4.7 µg/mL (Month 3) with Week 6 cTrough targets ranging 15-26 µg/mL depending on the outcome of interest. Higher AUC during induction for both infliximab and adalimumab was associated with deep remission, whereas rapid infliximab clearance at various timepoints was inversely associated with deep remission. Baseline predictors of rapid infliximab clearance included older age, low albumin, and elevations in body mass index, C-reactive protein, soluble CD64, and wPCDAI.
CONCLUSIONS: We identified PK/PD cut-points associated with deep remission and rapid infliximab clearance, providing actionable metrics to individualize induction dosing and optimize maintenance therapy for children starting anti-TNF therapy.
METHODS: Patients initiating infliximab or adalimumab were prospectively enrolled from four pediatric centers with longitudinal blood and stool biospecimens collected for one year. Deep remission was defined as a combination of weighted pediatric CD activity index (wPCDAI) < 12.5 and Simple Endoscopic Score-CD < 3. Trough concentrations (cTrough) were measured throughout the study. Drug exposure (area under the curve, AUC) and clearance were estimated using drug-specific population PK models and Bayesian estimation using nonlinear mixed-effects modeling (NONMEM).
RESULTS: Deep remission was achieved in 34/70 (48.6%) with no difference in outcomes between biologics. Infliximab cTrough thresholds associated with deep remission were 33 µg/mL (Week 2), 15 µg/mL (Week 6), and 4.7 µg/mL (Month 3) with Week 6 cTrough targets ranging 15-26 µg/mL depending on the outcome of interest. Higher AUC during induction for both infliximab and adalimumab was associated with deep remission, whereas rapid infliximab clearance at various timepoints was inversely associated with deep remission. Baseline predictors of rapid infliximab clearance included older age, low albumin, and elevations in body mass index, C-reactive protein, soluble CD64, and wPCDAI.
CONCLUSIONS: We identified PK/PD cut-points associated with deep remission and rapid infliximab clearance, providing actionable metrics to individualize induction dosing and optimize maintenance therapy for children starting anti-TNF therapy.