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 (E_max) 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 E_max, 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.

中文翻译：

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对贝洛单抗浓度和CDI复发的暴露-反应关系进行时间事件分析。

贝佐洛单抗是一种批准用于预防艰难梭菌复发的单克隆抗体感染（rCDI）。在先前对贝洛酮单抗暴露和rCDI的暴露-应答（ER）分析中，基于两项接受安慰剂或贝洛酮单抗10 mg / kg的参与者的两项3期试验的数据，rCDI被视为二元终点，被中断的受试者归因于因为没有rCDI，导致rCDI率和贝洛昔单抗暴露之间出现明显的E-R趋势。因此，采用事件发生时间（TTE）分析来研究E-R关系，从而说明发生rCDI和参与者中断的时间。建立了一个TTE模型，该模型应用了随时间变化的危害函数并基于rCDI，中止或研究结束对数据进行了右删失。评估暴露效应和协变量效应是影响危害的预测因子。TTE模型由随年龄变化的Gompertz函数组成，艰难梭菌毒素B（IgG-B），CDI病史，住院，性别，查尔森合并症指数以及同时使用影响危害的全身性抗生素。暴露效应的特征是对基线参数具有最大效应（E _max）E–R关系，并且发现在10 mg / kg剂量下达到的贝佐洛单抗暴露处于E–R曲线的平稳期。内源性IgG-B显着影响了E _max，表明与高滴度参与者相比，低滴度参与者从贝佐洛单抗治疗中受益更大。结果支持先前的E–R分析的结论，其中以10 mg / kg剂量获得的暴露量处于E–R曲线的平稳期。