Optimising infliximab induction dosing for patients with ulcerative colitis.

Area of Science:

• Pharmacology
• Gastroenterology
• Clinical Pharmacy

Background:

• Therapeutic failure of infliximab for ulcerative colitis is a persistent clinical challenge.
• While therapeutic drug monitoring (TDM) is valuable in maintenance therapy, its role in induction therapy remains underexplored.
• Standard dosing may lead to primary nonresponse or underexposure in some patients.

Purpose of the Study:

• To develop a population pharmacokinetic-pharmacodynamic model for infliximab induction therapy.
• To identify the optimal exposure metric that predicts mucosal healing in ulcerative colitis patients.
• To construct an exposure-response (ER) model for model-based dose optimization during induction.

Main Methods:

• A population pharmacokinetic model was developed using 583 samples from 204 patients.
• An exposure-response logistic regression model was built using data from 159 patients to link infliximab exposure to mucosal healing (Mayo endoscopic subscore transitions).
• The cumulative area under the infliximab concentration-time curve until endoscopy (CAUCendoscopy) was identified as the key exposure metric.

Main Results:

• A 1-compartment pharmacokinetic model best described infliximab exposure, influenced by covariates like C-reactive protein, albumin, and baseline disease severity.
• The CAUCendoscopy was confirmed as the best predictor of mucosal healing.
• The model predicted that 70% of patients could achieve mucosal healing with a target CAUCendoscopy of 3752 mg/L*day.

Conclusions:

• TDM-based dose individualization targeting CAUCendoscopy offers a promising strategy to enhance infliximab effectiveness during induction therapy.
• This approach has the potential to improve outcomes for ulcerative colitis patients by optimizing drug exposure.
• Model-based dose finding can address therapeutic failures associated with standard infliximab induction regimens.