Implementation of infliximab dosage regimen stratification through generalization/validation of rapid concentration-determining assays and generation of population-based pharmacokinetic/pharmacodynamic models

The market introduction of Remicade® (infliximab, IFX) triggered a revolution in the treatment of patients with inflammatory bowel disease, substantially increasing their quality of life. However, a significant percentage of these patients experiences loss of response (LOR), hampering therapeutic effectiveness. One mechanism causing LOR is increased drug clearance, resulting in subtherapeutic drug concentrations. Empirically, when a patient becomes refractory to IFX, treatment is intensified and if this fails, gastroenterologists switch to another tumor necrosis factor-alpha (TNF) antagonist. However, patient-specific factors may influence the pharmacokinetics (PK) of IFX. Therefore, instead of this one size fits all dosing strategy, we postulate a stratified dosing strategy to deal with LOR. Since it is important to take into account patient factors affecting the PK, this new strategy implies a testing-based approach that relies on therapeutic drug monitoring (TDM). Population PK modeling will be used to identify demographical, biological and clinical covariates that influence the PK, helping to explain the observed pharmacokinetic and pharmacodynamic variability in the population. Then, single predictive models, that incorporate identified covariates, will be generated to predict individualized drug dosing regimes and dose adjustments. The predicted personalized dosing algorithm should minimize variances in drug exposure to achieve a favorable impact on efficacy and safety.

Keywords:infliximab

Disciplines:Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences