Transplanted human organoids empower PK/PD assessment of drug candidate for the clinic

Pharmacokinetic/pharmacodynamic (PK/PD) studies are an essential component of pre-clinical drug discovery. Current best approaches for PK/PD studies, including the analysis of novel kidney disease targeting therapeutic agents, are limited to animal models with unclear translatability to the human condition. To address this challenge, we developed a novel approach for PK/PD studies using transplanted human kidney organoids. We performed PK studies with GFB-887, an investigational new drug now in Phase 2 trials. Orally dosed GFB-887 to athymic rats that had undergone organoid transplantation resulted in measurable drug exposure in human transplanted organoids. Importantly, we established the efficacy of orally dosed GFB-887 in PD studies, where quantitative analysis showed significant protection of kidney filter cells in human organoids and endogenous rat host kidneys. This widely applicable approach demonstrates, for the first time, feasibility of using transplanted human organoids in PK/PD studies, empowering organoids to revolutionize drug discovery.药代动力学/药效动力学（Pharmacokinetic/Pharmacodynamic，PK/PD）研究是临床前药物研发的核心组成部分。当前主流的PK/PD研究方法（涵盖新型肾病靶向治疗药物的相关分析）仅能依托动物模型开展，但其向人类疾病状态的转化可行性仍不明确。为应对这一挑战，我们开发了一种基于移植人类肾脏类器官（human kidney organoids）的新型PK/PD研究方案。我们以现已进入Ⅱ期临床试验的研究性新药GFB-887为对象开展了PK研究：对接受类器官移植的无胸腺大鼠口服给予GFB-887后，可在移植的人类类器官中检测到可量化的药物暴露量。尤为关键的是，我们在PD研究中证实了口服GFB-887的药效：定量分析结果显示，其可对人类类器官及大鼠内源宿主肾脏中的肾脏滤过细胞产生显著保护作用。这一具备广泛适用性的方法首次证明了在PK/PD研究中使用移植人类类器官的可行性，有望推动类器官技术彻底革新药物研发进程。