Population pharmacokinetics and exposure–response of anti‐programmed cell death protein‐1 monoclonal antibody dostarlimab in advanced solid tumours

分配量 医学 药代动力学 人口 协变量 逻辑回归 白蛋白 不利影响 内科学 药理学 统计 数学 环境卫生
作者
Murad Melhem,Eva Hanze,Sharon Lu,Oskar Alskär,Sandra Visser,Yash Gandhi
出处
期刊:British Journal of Clinical Pharmacology [Wiley]
卷期号:88 (9): 4142-4154 被引量:16
标识
DOI:10.1111/bcp.15339
摘要

Aim Develop a population pharmacokinetic (PopPK) model to characterise the pharmacokinetics (PK) of anti‐programmed cell death protein‐1 (PD‐1) antibody dostarlimab, identify covariates of clinical relevance, and investigate efficacy/safety exposure–response (ER) relationships. Methods A PopPK model was developed using Phase 1 GARNET (NCT02715284) trial data for dostarlimab (1, 3 or 10 mg kg −1 every 2 wk; 500 mg every 3 wk or 1000 mg every 6 wk; 500 mg every 3 wk × 4 then 1000 mg every 6 wk [recommended regimen]) serum concentrations over time. Concentration–time data were analysed using nonlinear mixed effects modelling with standard stepwise covariate modelling. ER was explored for treatment‐related adverse events and overall response rate (ORR) using logistic regression. Results PopPK model/adverse event ER analyses included 546 patients (ORR ER analysis n = 362). Dostarlimab PK was well described by a 2‐compartment model with time‐dependent linear elimination. Time‐dependent clearance decreased over time to a maximum of 14.9%. At steady state, estimated dostarlimab geometric mean coefficient of variation % clearance was 0.179 (30.2%) L d −1 ; volume of distribution was 5.3 (14.2%) L; terminal elimination half‐life was 23.5 (22.4%) days. Statistically significant covariates were age, body weight, sex, time‐varying albumin and alanine aminotransferase for clearance; body weight, albumin and sex for volume of distribution of the central compartment. Hepatic or renal impairment did not affect PK. There were no clinically significant ER relationships. Conclusion Dostarlimab PK parameters are similar to other anti‐programmed cell death protein‐1 antibodies. The clinical impact of covariates on exposure was limited‐to‐moderate, supporting recommended dostarlimab monotherapy therapeutic dosing.
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