title: Pharmacokinetics, pharmacodynamics, safety, and tolerability of JNJ-38431055, a novel GPR119 receptor agonist and potential antidiabetes agent, in healthy male subjects.
abstract: The incidence of type 2 diabetes mellitus is increasing worldwide. Several G-protein-coupled receptor agonists are being studied for their efficacy as antidiabetes agents. JNJ-38431055 is a novel, potent, and orally available selective agonist of the glucose-dependent insulinotropic (GPR119) receptor. Double-blind, randomized, placebo-controlled studies were conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of JNJ-38431055 (2.5-800 mg) in healthy male volunteers. The systemic exposure of JNJ-38431055 in plasma increased in proportion to the dose and was not influenced by coadministration of food. The terminal elimination half-life was ~13 h when administered as an oral suspension formulation. JNJ-38431055 was well tolerated and was not associated with hypoglycemia. As compared with placebo, single-dose oral JNJ-38431055 increased postmeal plasma glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) concentrations but did not significantly decrease glucose excursion or increase insulin secretion. However, in a graded glucose infusion study, JNJ-38431055 was shown to induce a higher insulin secretion rate (ISR) relative to placebo at elevated plasma glucose levels. These studies provide evidence for the potential efficacy of JNJ-38431055 as an antidiabetes agent in humans.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Spring House, Pennsylvania, 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: D C
authors.initials: DC
authors.lastname: Polidori
authors.forename: E
authors.initials: E
authors.lastname: Vets
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*; D004311:Double-Blind Method; D005749:Gastric Inhibitory Polypeptide / Q000097:blood / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D019894:Peptide YY / Q000097:blood / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*
chemical_list: D001786:Blood Glucose; C519854:GPR119 protein, human; D007004:Hypoglycemic Agents; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D019894:Peptide YY; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1