Population pharmacokinetic modeling and simulation for assessing renal impairment effect on the pharmacokinetics of mirogabalin.

A population pharmacokinetic model was developed to describe plasma concentrations of mirogabalin and lactam metabolite, obtained following a single oral dose of 5 mg mirogabalin to subjects with varying degrees of renal function.A 2-compartment model was used for both mirogabalin and lactam metabolite. Body weight was a significant covariate on volume of distribution of mirogabalin and lactam metabolite, whereas creatinine clearance significantly affected both renal and nonrenal clearance of mirogabalin. The total clearance of mirogabalin was decreased by 25%, 54%, and 76% in subjects with mild, moderate, and severe renal impairment, respectively, relative to normal controls. Simulation results showed that in comparison with the normal renal function group receiving mirogabalin 15 mg once or twice daily, dose reduction by 50% or 75% in subjects with moderate or severe renal impairment would produce similar AUCss values, but 37%-43% or 28%-32% lower Cmax,ss of mirogabalin. Predicted mirogabalin AUCss was 26% higher, whereas Cmax,ss was similar in subjects with mild renal impairment compared with those having normal renal function taking the same dose. Results support a dose reduction by 50% or 75% in subjects with moderate or severe renal impairment. No dose adjustment seemed necessary for subjects with mild renal impairment.