Prediction of the optimal dose of exenatide in patients with type 2 diabetes mellitus with renal impairment using physiologically based pharmacokinetic modeling

Although exenatide is approved for type 2 diabetes mellitus (T2DM) patients with mild to moderate renal impairment, specific dosing guidelines for this population remain undefined. To address this gap, we developed a physiologically-based pharmacokinetic (PBPK) model using PK-Sim & Mobi software, integrating target-mediated drug disposition (TMDD) to simulate exenatide's nonlinear pharmacokinetics in normal renal function. The model was extrapolated to renal impairment populations by adjusting physiological parameters and validated against clinical data. The plasma concentrations of exenatide predicted by the established PBPK models for populations with normal renal function and those with renal impairment were in high concordance with the observed values, with fold errors (FEs) of major PK parameters falling within the range of 0.5-2. After reducing simulated doses for the renal impairment population to 75%, 50%, and 25% of the 10 μg standard dose, AUC and C max were re-predicted to identify optimal doses that bring this population's PK parameters within the normal ranges. Based on our findings, we recommend a model-guided dosing strategy for T2DM patients with renal impairment, consisting of a initial dose of 2.5 μg twice daily, followed by 5-7.5 μg (mild impairment) or 5 μg (moderate impairment) twice daily for maintenance dose. This study suggests that, compared to T2DM patients with normal renal function, T2DM patients with renal impairment should begin at half the initial dose and also receive a reduced maintenance dose.