title: Non-linear increase in GLP-1 levels in response to DPP-IV inhibition in healthy adult subjects.
abstract: OBJECTIVE
  Dipeptidyl peptidase-IV (DPP-IV) inhibitors represent a new promising therapeutic intervention for the treatment of type 2 diabetes mellitus. The aim of this study was to investigate the effects of DPP-IV inhibition by PF-00734200, a potent competitive DPP-IV inhibitor, on the dynamics of DPP-IV activity and glucagon-like peptide-1 (GLP-1) kinetics in healthy adult subjects.
  
  
  METHODS
  This was a prospective randomized, crossover, placebo-controlled, ascending, single, oral dose study conducted at a clinical research centre. Twenty-seven healthy adult subjects were randomized to receive placebo or PF-00734200 with doses ranging from 0.3 to 300 mg (n = 9 per dose group). Pharmacokinetic and pharmacodynamic end points (DPP-IV activity and GLP-1) were measured prior to, and various times after, dosing.
  
  
  RESULTS
  PF-00734200 was well tolerated in all subjects. Pharmacokinetics (PK) data indicate that the drug was rapidly absorbed and declined in a biphasic fashion. Mean maximum concentration and area under concentration curve appeared to increase with doses proportionally. DPP-IV inhibition increased with PF-00734200 concentrations, which can be described by an E(max) model with EC50 approximately being 14 ng/ml. DPP-IV inhibition led to greater GLP-1 level accumulation compared with placebo. Plasma GLP-1 levels stimulated by meals were augmented by DPP-IV inhibition. However, the increase in GLP-1 with DPP-IV inhibition was non-linear and maximized at 10 mg, a dose which resulted in about 75% weighted average DPP-IV inhibition over 24 h and a 2.3-fold increase in GLP-1 over placebo. Moreover, even with near complete inhibition of DPP-IV for over 24 h at the highest PF-00734200 dose levels, the GLP-1 levels actually declined during the night compared with postdinner levels.
  
  
  CONCLUSIONS
  DPP-IV inhibition by PF-00734200 resulted in a non-linear increase in plasma GLP-1 level, suggesting GLP-1 levels may be limited by meal stimulus or by production capacity. In addition, GLP-1 level declined even during maximal DPP-IV inhibition, suggesting that there may be additional pathways of GLP-1 elimination other than DPP-IV enzymatic breakdown.
authors.affiliation: Department of Cardiovascular and Metabolic Diseases, Pfizer Inc., Groton, CT 06340, USA.
authors.forename: Haiqinq
authors.initials: H
authors.lastname: Dai
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Gustavson
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Preston
authors.forename: James D
authors.initials: JD
authors.lastname: Eskra
authors.forename: Roberto
authors.initials: R
authors.lastname: Calle
authors.forename: Boaz
authors.initials: B
authors.lastname: Hirshberg
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D018819:Dipeptidyl Peptidase 4 / Q000097:blood; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005215:Fasting; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D019518:Postprandial Period; D011446:Prospective Studies
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4