Purpose

This work describes a staged approach to the application of pharmacokinetic-pharmacodynamic (PK-PD) modeling in the voltage-gated sodium ion channel (NaV1.7) inhibitor drug discovery effort to address strategic questions regarding in vitro to in vivo translation of target modulation.

Methods

PK-PD analysis was applied to data from a functional magnetic resonance imaging (fMRI) technique to non-invasively measure treatment mediated inhibition of olfaction signaling in non-human primates (NHPs). Initial exposure-response was evaluated using single time point data pooled across 27 compounds to inform on in vitro to in vivo correlation (IVIVC). More robust effect compartment PK-PD modeling was conducted for a subset of 10 compounds with additional PD and PK data to characterize hysteresis.

Results

The pooled compound exposure-response facilitated an early exploration of IVIVC with a limited dataset for each individual compound, and it suggested a 2.4-fold in vitro to in vivo scaling factor for the NaV1.7 target. Accounting for hysteresis with an effect compartment PK-PD model as compounds advanced towards preclinical development provided a more robust determination of in vivo potency values, which resulted in a statistically significant positive IVIVC with a slope of 1.057 ± 0.210, R-squared of 0.7831, and p value of 0.006. Subsequent simulations with the PK-PD model informed the design of anti-nociception efficacy studies in NHPs.

Conclusions

A staged approach to PK-PD modeling and simulation enabled integration of in vitro NaV1.7 potency, plasma protein binding, and pharmacokinetics to describe the exposure-response profile and inform future study design as the NaV1.7 inhibitor effort progressed through drug discovery.

中文翻译：

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药代动力学-药效学建模在通知非人类灵长类动物体内NaV1.7抑制体内药理反应的翻译中的应用。

目的

这项工作描述了一种分阶段的方式来的药代动力学-药效学（PK-PD）的施加在电压-门控钠离子通道（NaV1.7）抑制剂药物发现关于努力地址战略问题建模体外向体内靶调制的翻译。

方法

PK-PD分析应用于功能磁共振成像（fMRI）技术的数据，以非侵入性方式测量治疗介导的非人类灵长类动物（NHP）嗅觉信号的抑制。使用汇总在27种化合物中的单个时间点数据来评估初始暴露反应，以告知体外与体内的相关性（IVIVC）。对10种化合物的子集进行了更鲁棒的效应区PK-PD建模，并附加了PD和PK数据以表征磁滞现象。

结果

合并的化合物暴露-反应促进了对每种化合物的有限数据集的IVIVC的早期探索，并且提出了NaV1.7靶标的2.4倍的体外-体内比例因子。随着化合物向临床前发展的进展，使用效应区室PK-PD模型解决了滞后现象，从而提供了更强大的体内效价测定方法，从而得出具有统计学意义的正IVIVC阳性斜率，斜率为1.057±0.210，R平方为0.7831，和p为0.006的值。随后用PK-PD模型进行的模拟为NHP中抗伤害感受功效研究的设计提供了依据。

结论

通过分阶段进行PK-PD建模和模拟，可以整合体外NaV1.7效价，血浆蛋白结合和药代动力学，以描述暴露-反应曲线，并随着NaV1.7抑制剂努力通过药物发现而发展，为将来的研究设计提供依据。