A time-to-event analysis of the exposure –response relationship for bezlotoxumab concentrations and CDI recurrence

AbstractBezlotoxumab is a monoclonal antibody approved for the prevention of recurrentClostridium difficile infection (rCDI). In a previous exposure –response (E–R) analysis of bezlotoxumab exposure and rCDI, based on data from two phase 3 trials in participants who received placebo or bezlotoxumab 10 mg/kg, rCDI was treated as a binary endpoint and discontinued subjects were imputed as not having rCDI, resulting in an apparent positive E– R trend between rCDI rates and bezlotoxumab exposure. Therefore, a time-to-event (TTE) analysis was applied to investigate the E–R relationship, accounting for the time to rCDI occurrence and participant discontinuation. A TTE model, applying a time-dependent hazard function and right-censoring of data based on rCDI, discontinuation, or study end was developed. Exposure effects and covariates effects were evaluated as predictors affecting the hazard. The TTE model consisted of a Gompertz function with age, endogenous immunoglobulin G toC. difficile toxin B (IgG-B), history of CDI, hospitalization, sex, Charlson Comorbidity Index, and concomitant use of systemic antibiotics affecting the hazard. Exposure effects were characterized with a maximum effect (Emax) E –R relationship on the baseline parameter, and bezlotoxumab exposures achieved at the 10 mg/kg dose were found to be on the plateau of the E–R curve. Endogenous IgG-B significantly impacted the Emax, indicating that low-titer participants derive a greater benefit from be...
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research