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To establish a population pharmacokinetic-pharmacodynamic (PK-PD) model of a novel glucagon-like peptide-1 (GLP-1) analogue in patients with type 2 diabetes mellitus (T2DM), using HbA1c levels after 52 weeks of treatment as the efficacy endpoint and based on a nonlinear mixed-effects model (NLME).
A population PK-PD linkage model was developed via the NLME approach, utilizing 1 967 plasma concentration data points and 1 813 observed HbA1c data points from 409 T2DM subjects enrolled in a Phase Ⅲ clinical trial. Model robustness and predictive performance were comprehensively validated using diagnostic plots, visual predictive check (VPC), and the Bootstrap method.
The PK characteristics were best described by a one-compartment model with first-order absorption and first-order elimination, while the PD model was a plasma concentration-driven indirect response model. Key parameters were estimated as follows: apparent volume of distribution (V/F)=11.28 L, apparent clearance (CL/F)=1.11 L·day-1, maximum inhibitory effect (Imax)=0.30, and half-maximal inhibitory concentration (IC50)=37.77 ng·mL-1. Covariate analysis revealed that baseline body weight was a significant factor affecting CL/F, and baseline HbA1c (group 1: HbA1c < 8.5%; group 2: HbA1c ≥ 8.5%) influenced the parameter kin.
The nonlinear mixed-effects model effectively utilizes sparsely sampled data, and the obtained PK-PD parameter estimates are robust and reliable.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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