Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
Q-fitter, Inc., Seoul, South Korea.
Br J Clin Pharmacol. 2024 Jan;90(1):286-298. doi: 10.1111/bcp.15891. Epub 2023 Sep 22.
The objective of this study was to characterize the pharmacokinetics (PK)/pharmacodynamics (PD) of DWP16001, a novel sodium-glucose cotransporter 2 inhibitor, and predict efficacious doses for the first-in-human study using various translational approaches.
A mechanistic PK/PD model was developed for DWP16001 using nonlinear mixed-effect modelling to describe animal PK/PD properties. Using allometry and in silico physiologically based equations, human PK parameters were predicted. Human PD parameters were scaled by applying interspecies difference and in vitro drug-specific factors. Human parameters were refined using early clinical data. Model-predicted PK and PD outcomes were compared to observations before and after parameter refinement.
The PK/PD model of DWP16001 was developed using a 2-compartment model with first-order absorption and indirect response. Efficacious doses of 0.3 and 2 mg of DWP16001 were predicted using human half-maximal inhibitory concentration values translated from Zucker Diabetic Fatty rats and normal rats, respectively. After parameter refinement, doses of 0.2 and 1 mg were predicted to be efficacious for each disease model, which improved the prediction results to within a 1.2-fold difference between the model prediction and observation.
This study predicted efficacious human doses of DWP16001 using population PK/PD modelling and a combined translational pharmacometrics approach. Early clinical data allowed the methods used to translate in vitro and in vivo findings to clinical PK/PD values for DWP16001 to be optimized. This study has shown that a refinement step can be readily applied to improve model prediction and further support the study design and conduct of a first-in-human study.
本研究旨在通过各种转化方法，描述新型钠-葡萄糖共转运蛋白 2 抑制剂 DWP16001 的药代动力学（PK）/药效学（PD）特征，并预测首次人体研究的有效剂量。
采用非线性混合效应模型对 DWP16001 的 PK/PD 进行了建模，以描述动物 PK/PD 特性。利用比例缩放和体内基于生理学的方程，预测了人体 PK 参数。通过应用种间差异和体外药物特异性因素对人体 PD 参数进行了缩放。利用早期临床数据对人体参数进行了优化。模型预测的 PK 和 PD 结果与参数优化前后的观察结果进行了比较。
DWP16001 的 PK/PD 模型是采用 2 室模型建立的，该模型具有一级吸收和间接反应。根据 Zucker 糖尿病肥胖大鼠和正常大鼠的半最大抑制浓度值，预测了 0.3 和 2 mg 的 DWP16001 有效剂量。经过参数优化后，预测 0.2 和 1 mg 的剂量分别对每种疾病模型有效，这将模型预测与观察结果之间的差异缩小到 1.2 倍以内。
本研究使用群体 PK/PD 建模和综合转化药理学方法预测了 DWP16001 的有效人体剂量。早期临床数据允许使用这些方法来优化将体外和体内研究结果转化为 DWP16001 的临床 PK/PD 值的方法。本研究表明，可以通过优化步骤来提高模型预测的准确性，并进一步支持首次人体研究的研究设计和实施。
