Efficacy and Safety Exposure–Response Analysis of Loncastuximab Tesirine in Patients with B cell non-Hodgkin Lymphoma

医学 内科学 药代动力学 加药 人口 单变量分析 比例危险模型 弥漫性大B细胞淋巴瘤 淋巴瘤 药效学 不利影响 胃肠病学 危险系数 逻辑回归 肿瘤科 药理学 多元分析 置信区间 环境卫生
作者
Brian T. Hess,William Townsend,Weiyun Z. Ai,Anastasios Stathis,Melhem Solh,Juan Pablo Alderuccio,David Ungar,Sam Liao,Lori Liao,Lisa Khouri,Xiaoyan Zhang,Joseph Boni
出处
期刊:Aaps Journal [Springer Science+Business Media]
卷期号:24 (1) 被引量:8
标识
DOI:10.1208/s12248-021-00660-3
摘要

We developed an integrated population pharmacokinetic model to investigate loncastuximab tesirine pharmacokinetics (PK) and exposure-response relationships for relapsed/refractory B cell non-Hodgkin lymphoma, including diffuse large B cell lymphoma (DLBCL). The model, based on the recommended dosing schedule (150 µg/kg every 3 weeks [Q3W] for 2 cycles; 75 µg/kg Q3W thereafter) and drug concentrations in phase 1 and 2 studies (DLBCL [n = 284], non-DLBCL [n = 44]), was used to characterize loncastuximab tesirine PK and evaluate exposure covariates. Relationships between exposure (pyrrolobenzodiazepine-conjugated antibody [cAb] cycle 1 average concentration) and (1) efficacy (including overall response rate [ORR; primary endpoint] and overall survival [OS]) and (2) grade ≥ 2 treatment-emergent adverse events were explored. Statistical analyses included univariate and multivariate logistic regression, Kaplan-Meier analysis, and Cox proportional hazard regression. cAb and total Ab were best described by a two-compartment linear model with time-dependent clearance. The cAb steady-state half-life increased to 20.6 days by ~ 15 weeks. cAb exposure was lower for low albumin, mild/moderate hepatic impairment, non-DLBCL subtypes, and Eastern Cooperative Oncology Group scores > 1. Significant positive associations were reported between exposure and ORR (p = 3.21E-6), OS (p = 0.0016), grade ≥ 2 increased gamma-glutamyltransferase, liver function test abnormalities, pain, and skin/nail reactions (p < 0.05). Low albumin, bulky disease, and mild/moderate hepatic impairment had a significant negative effect on OS (p < 0.01). Modeling supports the recommended loncastuximab tesirine dosing schedule. Although reduced exposure and efficacy were predicted for specific covariates (e.g., low albumin, mild/moderate hepatic impairment), dose increases are not recommended. Trial registration: NCT02669017 and NCT03589469.
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