Pharmacokinetic/pharmacodynamic modeling of GLP-1 in healthy rats.

PURPOSE

To provide a mechanism-based model to quantitatively describe GLP-1 pharmacokinetics (PK) and pharmacodynamics (PD) in rats.

METHODS

Intravenous (IV), infusion (IF), subcutaneous (SC), and intraperitoneal (IP) doses of GLP-1 were administered after glucose challenge in healthy Sprague-Dawley rats. Blood was analyzed for GLP-1, glucose, and insulin. The PK-PD modeling was performed with ADAPT 5. The concentration-response curve was generated and analyzed in comparison with other incretin-related therapeutics.

RESULTS

The PK of GLP-1 was described using a two-compartment model with a zero-order input accounting for endogenous GLP-1 synthesis. For SC and IP dosing, sequential zero-order and first-order absorption models reasonably described the rapid absorption process and flip-flop kinetics. In dynamics, GLP-1 showed insulinotropic effects (3-fold increase) after IV glucose challenge in a dose-dependent manner. The concentration-response curve was bell-shaped, which was captured using a biphasic two-binding site Adair model. Receptor binding of GLP-1 exhibited high capacity and low affinity kinetics for both binding sites (K(D) = 9.94 × 10(3) pM, K(2) = 1.56 × 10(-4) pM(-1)).

CONCLUSIONS

The PK of GLP-1 was linear and bi-exponential and its PD showed glucose-dependent insulinotropic effects. All profiles were captured by the present mechanistic model and the dynamic analysis yields several implications for incretin-related therapies.