Mechanistic insights into edoxaban's nonlinear pharmacokinetics and quinidine interaction via P-glycoprotein using physiologically based pharmacokinetic modeling.

Abstract

Edoxaban, a direct factor Xa inhibitor and known P-glycoprotein (P-gp) substrate, exhibits nonlinear increases in systemic exposure after oral administration and significant interaction with quinidine, a P-gp inhibitor. However, it remains unclear how P-gp in each organ contributes to these phenomena. We developed a physiologically based pharmacokinetic (PK) model to describe PK of edoxaban after oral (0.05-60 mg) and intravenous administration (30 mg), as well as its interaction with quinidine following edoxaban intravenously. Parameters were estimated using the Cluster Gauss-Newton method through top-down and middle-out approaches. Accurate description of renal clearance, which required incorporation of a hypothetical basolateral uptake process, underscoring the importance of unidentified renal transporters involved in edoxaban urinary secretion. Nonlinearity of dose-normalized area under blood concentration-time curve was highly sensitive to K_mP-gp, with intestinal unbound concentrations exceeding K_mP-gp at clinically relevant doses, consistent with intestinal P-gp saturation as the major driver of nonlinearity. In intravenous edoxaban-oral quinidine drug-drug interaction analysis, quinidine markedly reduced renal clearance and modestly increased hepatic availability, reflecting inhibition of renal and, to a lesser extent, hepatic P-gp. In conclusion, an edoxaban physiologically based PK model incorporating renal uptake transport enabled physiologically consistent description of renal clearance. Saturation of intestinal P-gp was identified as the primary contributor to nonlinear PK, while inhibition of renal P-gp was the main mechanism underlying the edoxaban intravenously administered with quinidine. These findings provide mechanistic insight into transporter contributions to edoxaban disposition and drug-drug interactions and highlight the importance of tissue-specific transporter processes in nonlinear pharmacokinetics. SIGNIFICANCE STATEMENT: Incorporating renal uptake transport is essential for mechanistically describing edoxaban renal clearance in physiologically based pharmacokinetic (PK) modeling. The model identifies intestinal P-glycoprotein saturation as the primary driver of nonlinear PK and renal P-glycoprotein inhibition as the major mechanism of the intraveous edoxaban-quinidine drug-drug interaction. These findings offer mechanistic insight into transporter contributions to edoxaban disposition and drug-drug interactions and emphasize the role of tissue-specific transport processes in nonlinear PK.