Inhibitor Linagliptin in Japanese Patients with Type 2 Diabetes Mellitus

treatment of type 2 diabetes mellitus (T2DM). Linagliptin exhibits non-linear pharmacokinetics (PK) due to saturable binding to plasma and tissue DPP-4. The aim of this study was to characterize the PK and PK/DPP-4 inhibition relationship of linagliptin in Japanese patients with T2DM using a population PK/DPP-4 model and to support the rationale for the therapeutic dose in Japanese patients by simulation. [Methods] Linagliptin plasma concentration and DPP-4 inhibition measurements from a placebo-controlled, parallel group multiple (28 days) dose trial that included 36 T2DM patients (18 patients each in 2.5 mg and 10 mg dose group) were used for analysis. Modeling was performed using FOCE INTERACTION estimation method implemented in NONMEM V. The linagliptin plasma concentration- and DPP-4 inhibition- time profiles were simulated for Japanese patients receiving 5 mg linagliptin once daily by the model established. [Results] Nonlinear PK of linagliptin in T2DM patients were well described by a 2-compartment model assuming concentration-dependent binding to DPP-4 in the central and peripheral compartment. Plasma DPP-4 inhibition was integrated in the model by relating the model-predicted DPP-4 occupancy with linagliptin linearly to DPP-4 inhibition. The simulation predicted that for the 5 mg dose group the trough DPP-4 inhibition at steady-state was 84.2%, which is higher than the target inhibition (≥80%) for an effective dose of DPP-4 inhibitor. In 2.