title: Effects of JNJ-38431055, a novel GPR119 receptor agonist, in randomized, double-blind, placebo-controlled studies in subjects with type 2 diabetes.
abstract: OBJECTIVE
  G-protein coupled receptor agonists are currently under investigation for their potential utility in patients with type 2 diabetes mellitus (T2DM). The objective was to determine the pharmacokinetics, pharmacodynamics, safety and tolerability of GPR119 agonist, JNJ-38431055 in T2DM subjects.
  
  
  METHODS
  This was a randomized, double-blind, placebo- and positive-controled, single-dose cross-over study and a randomized, double-blind, placebo-controled multiple-dose parallel design study. The study was conducted at 4 US research centres. Two different experiments involving 25 and 32 different subjects were performed in male and female subjects, aged 25-60 years, mean body mass index between 22 and 39.9 kg/m2 who had T2DM diagnosed 6 months to 10 years before screening. JNJ-38431055 (100 and 500 mg) or sitagliptin (100 mg) as a single-dose or JNJ-38431055 (500 mg) once daily for 14 consecutive days were tested. Effects on stimulated plasma glucose, insulin, C-peptide and incretin concentrations were pre-specified outcomes.
  
  
  RESULTS
  JNJ-38431055 was well tolerated and not associated with hypoglycaemia. Plasma systemic exposure of JNJ-38431055 increased as the dose increased, was approximately two-fold greater after multiple-dose administration, and attained steady-state after approximately 8 days. Compared with placebo, single-dose administration of oral JNJ-38431055 decreased glucose excursion during an oral glucose tolerance test, but multiple-dose administration did not alter 24-h weighted mean glucose. Multiple dosing of JNJ-38431055 increased post-meal total glucagon-like peptide 1 and gastric insulinotropic peptide concentrations compared to baseline.
  
  
  CONCLUSIONS
  These studies provide evidence of limited glucose lowering and incretin activity for JNJ-38431055 in subjects with T2DM.
authors.affiliation: Department of Clinical Development, Johnson & Johnson Pharmaceutical R&D, Raritan, NJ, USA. LKatz3@its.jnj.com
authors.forename: L B
authors.initials: LB
authors.lastname: Katz
authors.forename: J J
authors.initials: JJ
authors.lastname: Gambale
authors.forename: P L
authors.initials: PL
authors.lastname: Rothenberg
authors.forename: S R
authors.initials: SR
authors.lastname: Vanapalli
authors.forename: N
authors.initials: N
authors.lastname: Vaccaro
authors.forename: L
authors.initials: L
authors.lastname: Xi
authors.forename: T C
authors.initials: TC
authors.lastname: Sarich
authors.forename: P P
authors.initials: PP
authors.lastname: Stein
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000097:blood* / Q000187:drug effects; D005951:Glucose Tolerance Test; D006801:Humans; D054795:Incretins / Q000097:blood*; D008297:Male; D008875:Middle Aged; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D000068900:Sitagliptin Phosphate; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; C519854:GPR119 protein, human; D054795:Incretins; D011719:Pyrazines; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; D052216:Glucagon-Like Peptide 1; D000068900:Sitagliptin Phosphate