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document
Population pharmacokinetic/pharmacodynamic analysis of the DPP-4 inhibitor linagliptin in Japanese patients with type 2 diabetes mellitus . OBJECTIVES Linagliptin is a novel , highly selective and long acting DPP-4 inhibitor for the 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 2.5 mg dose group , steady-state DPP-4 inhibition of > 80 % was not maintained over 24 hours ( observed and simulated ) . CONCLUSIONS The nonlinear PK of linagliptin and its plasma DPP-4 inhibition in patients were well characterized by a target-mediated drug disposition model relating DPP-4 occupancy with linagliptin to DPP-4 inhibition . Simulations of plasma DPP-4 inhibition suggest that 5 mg linagliptin once daily is an appropriate therapeutic dose for Japanese patients with T2DM .
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Intervention_Pharmacological
Linagliptin
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Intervention_Pharmacological
Linagliptin
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Intervention_Pharmacological
linagliptin
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Intervention_Pharmacological
Linagliptin
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Intervention_Control
placebo-controlled
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Intervention_Pharmacological
linagliptin
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Intervention_Pharmacological
linagliptin
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Outcome_Physical
Plasma DPP-4 inhibition
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Outcome_Physical
DPP-4 inhibition
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Participant_Condition
with type 2 diabetes mellitus
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Participant_Condition
T2DM
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Participant_Sample-size
36
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Participant_Sample-size
18