A time-to-event analysis of the exposure–response relationship for bezlotoxumab concentrations and CDI recurrence
- 11 February 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Pharmacokinetics and Pharmacodynamics
- Vol. 47 (2), 121-130
- https://doi.org/10.1007/s10928-019-09660-5
Abstract
Bezlotoxumab is a monoclonal antibody approved for the prevention of recurrent Clostridium 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 to C. 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 bezlotoxumab treatment compared with high-titer participants. The results support the conclusions of the previous E–R analysis, where exposures achieved at the 10 mg/kg dose are on the plateau of the E–R curve.Keywords
Funding Information
- Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
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