在一项抗骨桥蛋白单克隆抗体首次人体研究中，评估其在皮肤和血液中的体内亲和力和靶标占有率。

In vivo affinity and target engagement in skin and blood in a first-time-in-human study of an anti-oncostatin M monoclonal antibody.

机构信息

ImmunoInflammation, GlaxoSmithKline, Stevenage, UK.

Clinical Pharmacology, GlaxoSmithKline, Stevenage, UK.

出版信息

Br J Clin Pharmacol. 2018 Oct;84(10):2280-2291. doi: 10.1111/bcp.13669. Epub 2018 Jul 12.

AIMS

The oncostatin M (OSM) pathway drives fibrosis, inflammation and vasculopathy, and is a potential therapeutic target for inflammatory and fibrotic diseases. The aim of this first-time-in-human experimental medicine study was to assess the safety, tolerability, pharmacokinetics and target engagement of single subcutaneous doses of GSK2330811, an anti-OSM monoclonal antibody, in healthy subjects.

METHODS

This was a phase I, randomized, double-blind, placebo-controlled, single-dose escalation, first-time-in-human study of subcutaneously administered GSK2330811 in healthy adults (NCT02386436). Safety and tolerability, GSK2330811 pharmacokinetic profile, OSM levels in blood and skin, and the potential for antidrug antibody formation were assessed. The in vivo affinity of GSK2330811 for OSM and target engagement in serum and skin blister fluid (obtained via a skin suction blister model) were estimated using target-mediated drug disposition (TMDD) models in combination with compartmental and physiology-based pharmacokinetic (PBPK) models.

RESULTS

Thirty subjects were randomized to receive GSK2330811 and 10 to placebo in this completed study. GSK2330811 demonstrated a favourable safety profile in healthy subjects; no adverse events were serious or led to withdrawal. There were no clinically relevant trends in change from baseline in laboratory values, with the exception of a reversible dose-dependent reduction in platelet count. GSK2330811 exhibited linear pharmacokinetics over the dose range 0.1-6 mg kg . The estimated in vivo affinity (nM) of GSK2330811 for OSM was 0.568 [95% confidence interval (CI) 0.455, 0.710] in the compartmental with TMDD model and 0.629 (95% CI 0.494, 0.802) using the minimal PBPK with TMDD model.

CONCLUSIONS

Single subcutaneous doses of GSK2330811 were well tolerated in healthy subjects. GSK2330811 demonstrated sufficient affinity to achieve target engagement in systemic circulation and target skin tissue, supporting the progression of GSK2330811 clinical development.

目的

抑瘤素 M（OSM）通路可驱动纤维化、炎症和血管病变，是治疗炎症和纤维化疾病的潜在治疗靶点。本首次人体实验医学研究的目的是评估健康受试者单次皮下给予 GSK2330811（一种抗 OSM 单克隆抗体）的安全性、耐受性、药代动力学和靶点结合情况。

方法

这是一项在健康成年人中进行的、随机、双盲、安慰剂对照、单次递增剂量的首次人体研究（NCT02386436），评估皮下给予 GSK2330811 的安全性和耐受性、GSK2330811 的药代动力学特征、血液和皮肤中的 OSM 水平，以及产生抗药物抗体的潜力。使用基于 TMDD 的模型结合房室和基于生理学的药代动力学（PBPK）模型，估算 GSK2330811 在血清和皮肤水疱液（通过皮肤抽吸水疱模型获得）中的体内亲和力以及靶点结合情况。

结果

该研究完成时，30 名受试者被随机分配接受 GSK2330811 治疗，10 名受试者接受安慰剂治疗。GSK2330811 在健康受试者中表现出良好的安全性特征；无严重不良事件或导致停药。除血小板计数呈剂量依赖性可逆下降外，实验室值从基线的变化无临床相关趋势。GSK2330811 在 0.1-6mg/kg 剂量范围内表现出线性药代动力学特征。在包含 TMDD 的房室模型中，GSK2330811 对 OSM 的体内亲和力估计值（nM）为 0.568（95%置信区间 0.455，0.710），而在包含 TMDD 的最小 PBPK 模型中为 0.629（95%置信区间 0.494，0.802）。