title: Population Pharmacokinetics and Pharmacodynamics of Linagliptin in Patients with Type 2 Diabetes Mellitus.
abstract: OBJECTIVE
  Linagliptin is a dipeptidyl peptidase (DPP)-4 inhibitor, used to treat type 2 diabetes mellitus (T2DM). Population pharmacokinetic and pharmacodynamic analyses were performed to characterize the impact of clinically relevant intrinsic/extrinsic factors (covariates) on linagliptin exposure and DPP-4 inhibition in patients with T2DM.
  
  
  METHODS
  Linagliptin plasma concentrations and DPP-4 activities were obtained from four studies (two phase 1, two phase 2b). Non-linear mixed-effects modelling techniques were implemented using NONMEM software. The covariates that were studied comprised demographic information and laboratory values, including liver enzyme levels and creatinine clearance, as well as study-related factors such as metformin co-treatment. Covariate effects on parameters describing the pharmacokinetics and pharmacokinetic/pharmacodynamic relationship were investigated using stepwise forward inclusion/backward elimination.
  
  
  RESULTS
  The pharmacokinetic analysis included 6,907 measurements of plasma linagliptin concentrations from 462 patients; the pharmacokinetic/pharmacodynamic analysis included 9,674 measurements of plasma DPP-4 activity and linagliptin plasma concentrations from 607 patients. The non-linear pharmacokinetics were described by a target-mediated drug disposition model accounting for the concentration-dependent binding of linagliptin to its target, DPP-4. The difference in exposure between the 5th and 95th percentiles of the covariate distributions and median was <20 % for each single covariate. Likewise, the impact of the covariates on both the half-maximum effect (EC50) and the concentration leading to 80 % DPP-4 inhibition was <20 %.
  
  
  CONCLUSIONS
  These analyses show that the investigated factors do not alter the pharmacokinetics and DPP-4 inhibitory activity of linagliptin to a clinically relevant extent and that dose adjustment is not necessary on the basis of factors including age, sex and weight.
authors: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany, silke.retlich@boehringer-ingelheim.com.
authors: Silke
authors: S
authors: Retlich
authors: Vincent
authors: V
authors: Duval
authors: Ulrike
authors: U
authors: Graefe-Mody
authors: Christian
authors: C
authors: Friedrich
authors: Sanjay
authors: S
authors: Patel
authors: Ulrich
authors: U
authors: Jaehde
authors: Alexander
authors: A
authors: Staab
mesh_terms: D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D000069476:Linagliptin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008687:Metformin / Q000493:pharmacokinetics; D008875:Middle Aged; D017711:Nonlinear Dynamics
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D000069476:Linagliptin; D008687:Metformin; D018819:Dipeptidyl Peptidase 4
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