Shanghai Qiangshi Information Technology Co., Ltd., Shanghai, 200120, China.
Hua Medicine (Shanghai) Limited, Shanghai, 201203, China.
Clin Pharmacokinet. 2023 Oct;62(10):1413-1425. doi: 10.1007/s40262-023-01286-8. Epub 2023 Aug 3.
Dorzagliatin is a first-in-class small molecule glucokinase activator (GKA) that improves pancreatic insulin secretion behavior and regulates hepatic glucose conversion in a glucose concentration-dependent manner. The primary objective of this study was to develop a population pharmacokinetic model of dorzagliatin to evaluate the influence of covariates, such as demographic characteristics and liver and kidney function, on the pharmacokinetics of dorzagliatin and provide a basis for medication guidance.
The pharmacokinetic data of dorzagliatin in this study came from six clinical trials. Based on the combined data, a population pharmacokinetic model of dorzagliatin was established using NONMEM software (ICON, MD, USA, version 7.4.3). The algorithm used was first-order conditional estimation with interaction (FOCEI). The dorzagliatin population pharmacokinetic modeling analysis included 1062 subjects and 7686 observable concentrations. Covariates, including age (AGE), sex (GEND), body weight (TBW), body mass index (BMI), body surface area (BSA), albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (CR), creatinine clearance (CRCL), and total bilirubin (TBIL), were screened using the forward-backward method. Model evaluation was performed using goodness-of-fit plots, prediction corrected visual prediction check (pcVPC), and bootstrap.
Concentration data of dorzagliatin in the dose range were best characterized by a two-compartment model with sequential zero-order then first-order absorption and first-order elimination. The final model estimated dorzagliatin data for typical male subjects (69 kg body weight, 18 U/L AST and 55 years old); the apparent total clearance (CL/F) was 10.4 L/h, apparent volume of central compartment distribution (V/F) was 80.6 L, inter-compartmental clearance (Q/F) was 3.02 L/h, apparent volume of peripheral compartment distribution (V/F) was 26.5 L, absorption rate constant (K) was 3.29 h, and duration of zero-order absorption (D) was 0.418 h. The inter-individual variation of CL/F, V/F, V/F, and D was 22.5%, 14.9%, 48.8%, and 82.8%, respectively.
The two-compartment linear pharmacokinetic model with zero- and first-order sequential absorption adequately described the pharmacokinetic characteristics of dorzagliatin. Body weight, aspartate aminotransferase, and age had a statistically significant effect on the CL/F of dorzagliatin. Body weight and sex had a statistically significant effect on V/F. However, considering the clinically insignificant changes in the magnitude of steady-state exposure caused by these covariates, as well as the minimal changes in the steady-state exposure for individuals with mild and moderate impaired hepatic function and all stages of renal impairment, dose adjustments based on the tested covariates or for specific populations are deemed unnecessary.
度拉糖肽是一种首创的小分子葡萄糖激酶激活剂（GKA），可改善胰腺胰岛素分泌行为，并以葡萄糖浓度依赖的方式调节肝葡萄糖转化。本研究的主要目的是建立度拉糖肽的群体药代动力学模型，以评估人口统计学特征和肝肾功能等因素对度拉糖肽药代动力学的影响，为用药指导提供依据。
本研究度拉糖肽的药代动力学数据来自 6 项临床试验。基于合并数据，采用 NONMEM 软件（ICON，MD，USA，版本 7.4.3）建立度拉糖肽的群体药代动力学模型。采用一阶条件估计法结合相互作用（FOCEI）。度拉糖肽群体药代动力学建模分析包括 1062 例受试者和 7686 个可观测浓度。采用前后向法筛选年龄（AGE）、性别（GEND）、体重（TBW）、体重指数（BMI）、体表面积（BSA）、白蛋白（ALB）、丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST）、血清肌酐（CR）、肌酐清除率（CRCL）和总胆红素（TBIL）等协变量。采用拟合度图、预测校正可视化预测检查（pcVPC）和 bootstrap 进行模型评估。
度拉糖肽在剂量范围内的浓度数据最好用两室模型描述，该模型具有顺序零级然后一级吸收和一级消除。最终模型估计了典型男性受试者（体重 69kg、AST 18U/L 和 55 岁）的度拉糖肽数据；表观总清除率（CL/F）为 10.4L/h，中央室分布容积（V/F）表观值为 80.6L，隔室间清除率（Q/F）为 3.02L/h，外周室分布容积（V/F）表观值为 26.5L，吸收速率常数（K）为 3.29h，零级吸收持续时间（D）为 0.418h。CL/F、V/F、V/F 和 D 的个体间变异分别为 22.5%、14.9%、48.8%和 82.8%。
具有零级和一级顺序吸收的两室线性药代动力学模型充分描述了度拉糖肽的药代动力学特征。体重、天门冬氨酸氨基转移酶和年龄对度拉糖肽的 CL/F 有统计学意义。体重和性别对 V/F 有统计学意义。然而，考虑到这些协变量引起的稳态暴露量的临床意义不大，以及轻度和中度肝功能损害以及所有阶段肾功能损害个体的稳态暴露量的微小变化，不需要基于所测试的协变量或特定人群进行剂量调整。
