PMID- 24393553
OWN - NLM
STAT- MEDLINE
DCOM- 20140904
LR  - 20221207
IS  - 1482-1826 (Electronic)
IS  - 1482-1826 (Linking)
VI  - 16
IP  - 5
DP  - 2013
TI  - Population pharmacokinetic/pharmacodynamic analysis of the DPP-4 inhibitor 
      linagliptin in Japanese patients with type 2 diabetes mellitus.
PG  - 708-21
AB  - 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.
FAU - Tadayasu, Yusuke
AU  - Tadayasu Y
AD  - Nippon Boehringer Ingelheim Co., Ltd. Medical Development Div.
FAU - Sarashina, Akiko
AU  - Sarashina A
FAU - Tsuda, Yasuhiro
AU  - Tsuda Y
FAU - Tatami, Shinji
AU  - Tatami S
FAU - Friedrich, Christian
AU  - Friedrich C
FAU - Retlich, Silke
AU  - Retlich S
FAU - Staab, Alexander
AU  - Staab A
FAU - Takano, Mikihisa
AU  - Takano M
LA  - eng
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Randomized Controlled Trial
PL  - Switzerland
TA  - J Pharm Pharm Sci
JT  - Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian 
      Society for Pharmaceutical Sciences, Societe canadienne des sciences 
      pharmaceutiques
JID - 9807281
RN  - 0 (Dipeptidyl-Peptidase IV Inhibitors)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Purines)
RN  - 0 (Quinazolines)
RN  - 3X29ZEJ4R2 (Linagliptin)
RN  - EC 3.4.14.5 (Dipeptidyl Peptidase 4)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Asian People
MH  - Diabetes Mellitus, Type 2/*metabolism
MH  - Dipeptidyl Peptidase 4/metabolism
MH  - Dipeptidyl-Peptidase IV Inhibitors/blood/*pharmacokinetics/pharmacology
MH  - Double-Blind Method
MH  - Female
MH  - Humans
MH  - Hypoglycemic Agents/blood/*pharmacokinetics/pharmacology
MH  - Linagliptin
MH  - Male
MH  - Middle Aged
MH  - *Models, Biological
MH  - Purines/blood/*pharmacokinetics/pharmacology
MH  - Quinazolines/blood/*pharmacokinetics/pharmacology
EDAT- 2014/01/08 06:00
MHDA- 2014/09/05 06:00
CRDT- 2014/01/08 06:00
PHST- 2014/01/08 06:00 [entrez]
PHST- 2014/01/08 06:00 [pubmed]
PHST- 2014/09/05 06:00 [medline]
AID - 10.18433/j3s304 [doi]
PST - ppublish
SO  - J Pharm Pharm Sci. 2013;16(5):708-21. doi: 10.18433/j3s304.