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 patients with type 2 diabetes mellitus (T2DM) with mild to moderate renal impairment, specific dosing guidelines for this population remain undefined. To address this gap, we developed a physiologically based pharmacokinetic model using PK-Sim & MoBi software, integrating target-mediated drug disposition 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 physiologically based pharmacokinetic models for populations with normal renal function and those with renal impairment were in high concordance with the observed values, with fold errors of major pharmacokinetic parameters falling within the 0.5- to 2-fold range. After reducing simulated doses for the renal impairment population to 75%, 50%, and 25% of the 10 μg standard dose, area under the concentration-time curve and C_max were re-predicted to identify optimal doses that bring this population's pharmacokinetic parameters within the normal ranges. On the basis of our findings, we recommend a model-guided dosing strategy for patients with T2DM with renal impairment, consisting of an 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 with patients with T2DM with normal renal function, patients with T2DM with renal impairment should begin at half the initial dose and also receive a reduced maintenance dose. SIGNIFICANCE STATEMENT: Exenatide is approved by the US Food and Drug Administration for patients with type 2 diabetes mellitus with mild to moderate renal impairment, but dosing guidelines are still lacking. This study developed and validated physiologically based pharmacokinetic models of exenatide in renal impairment. These new models close the evidence gap for optimal dosing in this population.