Model-based clinical pharmacology profiling and exposure-response relationships of the efficacy and biomarker of lebrikizumab in patients with moderate-to-severe asthma

作者：Rui Zhu, Yanan Zheng, Nathanael L. Dirks, Shweta Vadhavkar, Jin Y. Jin, Kun Peng, Cécile Holweg, Julie Olsson, John G. Matthews, Wendy S. Putnam · 发表于：Pulmonary Pharmacology & Therapeutics · 年份：2017 · DOI：10.1016/j.pupt.2017.08.010 · 被引用次数：18 · 研究领域：Asthma and respiratory diseases、Inhalation and Respiratory Drug Delivery、IL-33, ST2, and ILC Pathways

Lebrikizumab is a humanized monoclonal antibody that binds to interleukin-13 and has been evaluated as a treatment for moderate-to-severe asthma. Objectives of this work were to characterize lebrikizumab pharmacokinetics (PK), identify influential covariates, and graphically explore exposure-response relationships in moderate-to-severe asthmatics. Pooled PK data from 11 studies were used in the population PK model development. Full covariate modeling was used to evaluate the impact of pre-specified covariates. Response data (exacerbation rate, forced expiratory volume in 1 s [FEV1], and fractional exhaled nitric oxide [FeNO]) were obtained from moderate-to-severe asthmatics (n = 2148) who received placebo, lebrikizumab 37.5 mg or 125 mg every 4 weeks (Q4W) in two replicate phase 3 studies. Graphical exposure-response analyses were stratified by numerous covariates, including biomarker subgroups defined by serum periostin level and blood eosinophil count at baseline. Lebrikizumab PK was described by a two-compartment model with first-order absorption. Population typical values were estimated as 0.156 L/day for clearance (CL), 4.10 L for central volume (Vc), and 0.239 day−1 for absorption rate (ka), 85.6% for bioavailability (inter-subject variability: CL, 33.3%; Vc, 36.3%; ka, 40.8%). The estimated mean terminal half-life was 25.7 days. Body weight was the most influential covariate. Generally, the exposure-response analyses of FEV1 and FeNO showed increased response at higher...