Oral small-molecule GLP-1R agonist HDM1002 achieves bioequivalence across doses with minor food effect on Cmax.
Background
The global rise in type 2 diabetes and obesity necessitates effective, convenient treatments. Glucagon-like peptide-1 receptor (GLP-1R) agonists are highly effective, but most are injectables, posing adherence challenges. Oral small-molecule GLP-1R agonists represent a significant advancement, offering improved patient convenience and potentially broader access. Understanding their pharmacokinetics, including dose proportionality and food effects, is crucial for developing practical dosing regimens and ensuring consistent therapeutic efficacy.
Study Design
This single-center, randomized, open-label, single-dose, two-formulation, three-period, double-crossover phase I study enrolled 33 healthy Chinese volunteers. Subjects received three treatments with a 7-day washout: (A) two 100-mg HDM1002 tablets under fasting conditions; (B) a single 200-mg HDM1002 tablet under fasting conditions; and (C) a single 200-mg HDM1002 tablet following a high-fat meal. Plasma concentrations were measured using HPLC-MS/MS, and pharmacokinetic (PK) parameters were determined via non-compartmental analysis, focusing on Cmax, AUC0-t, and AUC0-∞.
Results
Under fasting conditions, HDM1002 demonstrated bioequivalence between the two 100-mg tablets and the single 200-mg tablet. The 90% confidence intervals (CI) for the geometric mean ratios (two 100-mg vs. one 200-mg tablet) were: Cmax 106.87% (91.42%, 124.92%), AUC0-t 99.64% (95.32%, 104.15%), and AUC0-∞ 99.55% (95.20%, 104.09%). All these CIs fell within the standard 80.00%-125.00% bioequivalence range. A high-fat meal modestly affected the 200-mg tablet's Cmax, with its 90% CI (fed vs. fasted) at 87.53% (76.88%, 99.66%), where the lower limit was slightly below 80.00%. However, overall exposure (AUC) was not significantly impacted by food: AUC0-t was 105.90% (99.80%, 112.37%) and AUC0-∞ was 106.01% (99.92%, 112.47%), both within the bioequivalence range.
No serious adverse events (AEs) occurred, indicating HDM1002 was well-tolerated and safe in this cohort.
Key Findings
- HDM1002 100mg and 200mg oral tablets were bioequivalent under fasting conditions.
- Fasting Cmax ratio for 100mg vs. 200mg was 106.87% (90% CI: 91.42%-124.92%).
- Fasting AUC0-t ratio for 100mg vs. 200mg was 99.64% (90% CI: 95.32%-104.15%).
- A high-fat meal modestly reduced HDM1002 200mg Cmax, with a 90% CI lower limit of 76.88%.
- A high-fat meal did not significantly affect HDM1002 200mg overall exposure (AUC0-t ratio 105.90%).
Why It Matters
The development of an oral GLP-1R agonist like HDM1002 is a significant step towards more patient-friendly treatments for type 2 diabetes and obesity, potentially improving adherence compared to injectables. HDM1002's bioequivalence between different tablet strengths provides flexibility in dosing and manufacturing. While a high-fat meal slightly reduced Cmax, the consistent overall exposure (AUC) suggests that HDM1002 can be taken with or without food without significantly compromising its therapeutic efficacy over time. This finding simplifies patient instructions and enhances the practical applicability of HDM1002 in a real-world setting, paving the way for further clinical development.
hdm1002
glp-1r-agonist
oral
pharmacokinetics
bioequivalence
food-effect