Drug Clinical Trial Center, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China.
Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China.
CPT Pharmacometrics Syst Pharmacol. 2023 Apr;12(4):487-499. doi: 10.1002/psp4.12934. Epub 2023 Mar 8.
Type 2 diabetes mellitus (T2DM) agent sodium-glucose co-transporter 2 (SGLT2) inhibitors show special benefits in reducing body weight and heart failure risks. To accelerate clinical development for novel SGLT2 inhibitors, a quantitative relationship among pharmacokinetics, pharmacodynamics, and disease end points (PK/PD/end points) in healthy subjects and patients with T2DM was developed. PK/PD/end point data in published clinical studies for three globally marketed SGLT2 inhibitors (dapagliflozin, canagliflozin, and empagliflozin) were collected according to pre-set criteria. Overall, 80 papers with 880 PK, 27 PD, 848 fasting plasma glucose (FPG), and 1219 hemoglobin A1c (HbA1c) data were collected. A two-compartmental model with Hill's equation was utilized to capture PK/PD profiles. A novel translational biomarker, the change of urine glucose excretion (UGE) from baseline normalized by FPG (ΔUGE ) was identified to bridge healthy subjects and patients with T2DM with different disease statuses. ΔUGE was found to have a similar maximum increase with different half-maximal effective concentration values of 56.6, 2310, and 841 mg/mL·h for dapagliflozin, canagliflozin, and empagliflozin respectively. ΔUGE will change FPG based on linear function. HbA1c profiles were captured by indirect response model. Additional placebo effect was also considered for both end points. The PK/ΔUGE /FPG/HbA1c relationship was validated internally using diagnostic plots and visual assessment and further validated externally using the fourth globally approved same-in-class drug (ertugliflozin). This validated quantitative PK/PD/end point relationship offers novel insight into long-term efficacy prediction for SGLT2 inhibitors. The novelty identified ΔUGE could make the comparison of different SGLT2 inhibitors' efficacy characteristics easier, and achieve early prediction from healthy subjects to patients.
2 型糖尿病（T2DM）药物钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂在降低体重和心力衰竭风险方面具有特殊益处。为了加速新型 SGLT2 抑制剂的临床开发，在健康受试者和 T2DM 患者中建立了药代动力学、药效学和疾病终点（PK/PD/终点）之间的定量关系。根据预设标准，收集了三种已上市的全球 SGLT2 抑制剂（达格列净、卡格列净和恩格列净）的已发表临床研究中的 PK/PD/终点数据。总共收集了 80 篇论文，其中 880 项 PK 数据、27 项 PD 数据、848 项空腹血糖（FPG）数据和 1219 项糖化血红蛋白（HbA1c）数据。采用双室模型和 Hill 方程来捕获 PK/PD 曲线。发现一种新的转化生物标志物，即通过 FPG 标准化的基线尿葡萄糖排泄变化（ΔUGE），以桥接健康受试者和不同疾病状态的 T2DM 患者。发现 ΔUGE 与不同的半有效浓度值具有相似的最大增加，达格列净、卡格列净和恩格列净的半有效浓度值分别为 56.6、2310 和 841mg/mL·h。ΔUGE 将根据线性函数改变 FPG。HbA1c 曲线通过间接响应模型捕获。两个终点都考虑了额外的安慰剂效应。使用诊断图和直观评估对内进行了 PK/ΔUGE/FPG/HbA1c 关系的内部验证，并使用第四种全球批准的同类药物（ertugliflozin）进行了外部验证。经过验证的定量 PK/PD/终点关系为 SGLT2 抑制剂的长期疗效预测提供了新的见解。所鉴定的新颖 ΔUGE 可以使不同 SGLT2 抑制剂疗效特征的比较更加容易，并实现从健康受试者到患者的早期预测。
