Treatment Targets Should Influence Choice of Infliximab Dose Intensification Strategy in Inflammatory Bowel Disease: A Pharmacokinetic Simulation Study

Background The optimal infliximab dose intensification strategy to address loss of response associated with subtherapeutic infliximab trough levels remains uncertain, as does whether post-intensification trough and treatment targets should influence this decision. Objectives This pharmacokinetic sim...

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Bibliographic Details
Published in:BioDrugs : clinical immunotherapeutics, biopharmaceuticals, and gene therapy biopharmaceuticals, and gene therapy, 2024-09, Vol.38 (5), p.691-702
Main Authors: Srinivasan, Ashish, van Langenberg, Daniel, De Cruz, Peter, Segal, Jonathan, Vasudevan, Abhinav, Upton, Richard N.
Format: Article
Language:English
Subjects:
Antibodies
Binomial distribution
Biomedical and Life Sciences
Biomedicine
Cancer Research
Crohn's disease
Crohns disease
Dosage
Endoscopy
Fistula
Fistulae
Inflammatory bowel disease
Inflammatory bowel diseases
Infliximab
Molecular Medicine
Monoclonal antibodies
Normal distribution
Original
Original Research Article
Pharmacokinetics
Pharmacotherapy
Proteins
Remission
Remission (Medicine)
Simulation
Tumor necrosis factor-α
Ulcerative colitis
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Summary:Background The optimal infliximab dose intensification strategy to address loss of response associated with subtherapeutic infliximab trough levels remains uncertain, as does whether post-intensification trough and treatment targets should influence this decision. Objectives This pharmacokinetic simulation study aimed to identify infliximab dose intensification strategies capable of achieving post-intensification infliximab trough thresholds associated with clinical and objective treatment targets in Crohn’s disease and ulcerative colitis. Methods A validated pharmacokinetic infliximab model, applied to 200 simulated patients, identified those with subtherapeutic ( 7.50 mg/L, Crohn’s disease > 9.70 mg/L) was the primary outcome, with perianal fistula healing (Crohn’s disease > 10.10 mg/L) and clinical improvement (ulcerative colitis > 3.70 mg/L, Crohn’s disease > 7.00mg/L) evaluated as secondary outcomes. All outcomes were stratified by intensity of dose intensification, with standard (≤ 10 mg/kg 8-weekly or 5 mg/kg 4-weekly; n  = 5) and intensive (> 10 mg/kg 8-weekly or 5 mg/kg 4-weekly; n  = 5) dosing strategies defined, respectively. Results The median pre-intensification infliximab trough level was 0.91 mg/L (interquartile range 1.37). Intensive dosing strategies were more likely to achieve infliximab trough concentrations associated with endoscopic remission (ulcerative colitis 36.48% vs. 10.80%, Crohn’s disease 25.98 vs. 4.68%), perianal fistula healing (24.52% vs. 4.36%) and clinical improvement (ulcerative colitis 61.90% vs. 34.86%, Crohn’s disease 40.32 vs. 12.08%) than standard intensification strategies (all p  
ISSN:1173-8804
1179-190X
1179-190X
DOI:10.1007/s40259-024-00673-2