Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Cambridge Ltd, Cambridge, UK.
Pharm Res. 2020 Aug 5;37(8):164. doi: 10.1007/s11095-020-02893-x.
TAK-831 is a highly selective and potent inhibitor of D-amino acid oxidase (DAAO) currently under clinical development for schizophrenia. In this study, a mechanistic multilayer quantitative model that parsimoniously connects pharmacokinetics (PK), target occupancy (TO) and D-serine concentrations as a pharmacodynamic (PD) readout was established in mice.
PK, TO and PD time-profiles were obtained in mice and analyzed by mechanistic binding kinetics model connected with an indirect response model in a step wise fashion. Brain distribution was investigated to elucidate a possible mechanism driving the hysteresis between PK and TO.
The observed nonlinear PK/TO/PD relationship was well captured by mechanistic modeling framework within a wide dose range of TAK-831 in mice. Remarkably different brain distribution was observed between target and reference regions, suggesting that the target-mediated slow binding kinetics rather than slow penetration through the blood brain barrier caused the observed distinct kinetics between PK and TO.
A quantitative mechanistic model for concentration- and time-dependent nonlinear PK/TO/PD relationship was established for TAK-831 in mice with accounting for possible rate-determining process. The established mechanistic modeling framework will provide a quantitative means for multilayer biomarker-assisted clinical development in multiple central nervous system indications.
TAK-831 是一种高度选择性和有效的 D-氨基酸氧化酶（DAAO）抑制剂，目前正在开发用于精神分裂症。本研究在小鼠中建立了一种机制多层定量模型，该模型简洁地将药代动力学（PK）、靶标占有率（TO）和 D-丝氨酸浓度作为药效学（PD）读出连接起来。
在小鼠中获得 PK、TO 和 PD 时间曲线，并通过机械结合动力学模型与间接反应模型逐步进行分析。研究了脑分布，以阐明驱动 PK 和 TO 之间滞后的可能机制。
在小鼠中，TAK-831 的广泛剂量范围内，观察到的非线性 PK/TO/PD 关系通过机制建模框架得到了很好的捕捉。在靶区和参照区之间观察到明显不同的脑分布，这表明是靶介导的缓慢结合动力学而不是通过血脑屏障的缓慢渗透导致了观察到的 PK 和 TO 之间的明显动力学差异。
为 TAK-831 在小鼠中建立了一个定量的、基于浓度和时间的非线性 PK/TO/PD 关系的机制模型，该模型考虑了可能的限速过程。所建立的机制建模框架将为多个中枢神经系统适应症的基于多层生物标志物的临床开发提供一种定量手段。
