title: Population pharmacokinetic/pharmacodynamic analysis of the DPP-4 inhibitor linagliptin in Japanese patients with type 2 diabetes mellitus.
abstract: OBJECTIVE
  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.
authors.affiliation: Nippon Boehringer Ingelheim Co., Ltd. Medical Development Div.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tadayasu
authors.forename: Akiko
authors.initials: A
authors.lastname: Sarashina
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Shinji
authors.initials: S
authors.lastname: Tatami
authors.forename: Christian
authors.initials: C
authors.lastname: Friedrich
authors.forename: Silke
authors.initials: S
authors.lastname: Retlich
authors.forename: Alexander
authors.initials: A
authors.lastname: Staab
authors.forename: Mikihisa
authors.initials: M
authors.lastname: Takano
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000069476:Linagliptin; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011687:Purines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011799:Quinazolines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin; D018819:Dipeptidyl Peptidase 4