Hood John, González-García Ignacio, White Nicholas, Marshall Leeron, Dubois Vincent F S, Vicini Paolo, Baverel Paul G
Clinical Pharmacology and Quantitative Pharmacology, AstraZeneca, Cambridge CB21 6GH, UK.
Salford Royal Foundation Trust, Salford M6 8HD, UK.
Pharmaceutics. 2021 Apr 9;13(4):519. doi: 10.3390/pharmaceutics13040519.
A sequential pharmacokinetic (PK) and pharmacodynamic (PD) model was built with Nonlinear Mixed Effects Modelling based on data from a first-in-human trial of a novel biologic, MEDI7836. MEDI7836 is a human immunoglobulin G1 lambda (IgG1λ-YTE) monoclonal antibody, with an Fc modification to reduce metabolic clearance. MEDI7836 specifically binds to, and functionally neutralizes interleukin-13. Thirty-two healthy male adults were enrolled into a dose-escalation clinical trial. Four active doses were tested (30, 105, 300, and 600 mg) with 6 volunteers enrolled per cohort. Eight volunteers received placebo as control. Following single subcutaneous administration (SC), individual time courses of serum MEDI7836 concentrations, and the resulting serum IL13 modulation in vivo, were quantified. A binding pharmacokinetic-pharmacodynamic (PK-PD) indirect response model was built to characterize the exposure-driven modulation of the target over time by MEDI7836. While the validated bioanalytical assay specification quantified the level of free target (i.e., a free IL13 assay), emerging clinical data suggested dose-dependent increase in systemic IL13 concentration over time, indicative of a total IL13 assay. The target time course was modelled as a linear combination of free target and a percentage of the drug-target complex to fit the clinical data. This novel PK-PD modelling approach integrates independent knowledge about the assay characteristics to successfully elucidate apparently complex observations.
基于新型生物制剂MEDI7836首次人体试验的数据，采用非线性混合效应模型建立了序贯药代动力学（PK）和药效动力学（PD）模型。MEDI7836是一种人免疫球蛋白G1λ（IgG1λ-YTE）单克隆抗体，其Fc经过修饰以降低代谢清除率。MEDI7836特异性结合并功能性中和白细胞介素-13。32名健康成年男性受试者被纳入剂量递增临床试验。试验了4个活性剂量（30、105、300和600mg），每个队列招募6名志愿者。8名志愿者接受安慰剂作为对照。单次皮下给药（SC）后，对血清MEDI7836浓度的个体时间进程以及体内由此产生的血清IL13调节进行了定量。建立了一个结合药代动力学-药效动力学（PK-PD）间接反应模型，以表征MEDI7836随时间对靶点的暴露驱动调节。虽然经过验证的生物分析测定规范对游离靶点水平进行了定量（即游离IL13测定），但新出现的临床数据表明，全身IL13浓度随时间呈剂量依赖性增加，这表明是总IL13测定。将靶点时间进程建模为游离靶点和药物-靶点复合物百分比的线性组合，以拟合临床数据。这种新颖的PK-PD建模方法整合了有关测定特征的独立知识，以成功阐明明显复杂的观察结果。
