Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of JNJ-38431055, a Novel GPR119 Receptor Agonist and Potential Antidiabetes Agent, in Healthy Male Subjects

被引:40
作者
Katz, L. B. [1 ]
Gambale, J. J. [1 ]
Rothenberg, P. L. [2 ]
Vanapalli, S. R. [2 ]
Vaccaro, N. [2 ]
Xi, L. [1 ]
Polidori, D. C. [3 ]
Vets, E. [4 ]
Sarich, T. C. [2 ]
Stein, P. P. [2 ]
机构
[1] Johnson & Johnson Pharmaceut Res & Dev LLC, Spring House, PA USA
[2] Johnson & Johnson Pharmaceut Res & Dev LLC, Raritan, NJ USA
[3] Johnson & Johnson Pharmaceut Res & Dev LLC, La Jolla, CA USA
[4] SGS Life Sci Serv, Antwerp, Belgium
关键词
GLUCAGON-LIKE PEPTIDE-1; PROTEIN-COUPLED RECEPTOR; BETA-CELL SENSITIVITY; INSULIN-SECRETION; GLYCEMIC CONTROL; TYPE-2; GLUCOSE; GLP-1; HYPERGLYCEMIA; SINGLE;
D O I
10.1038/clpt.2011.169
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 similar to 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.
引用
收藏
页码:685 / 692
页数:8
相关论文
共 42 条
[1]   GLP-1: physiological effects and potential therapeutic applications [J].
Aaboe, Kasper ;
Krarup, Thure ;
Madsbad, Sten ;
Holst, Jens Juul .
DIABETES OBESITY & METABOLISM, 2008, 10 (11) :994-1003
[2]   EFFECT OF PEPTIDE-YY ON GASTRIC, PANCREATIC, AND BILIARY FUNCTION IN HUMANS [J].
ADRIAN, TE ;
SAVAGE, AP ;
SAGOR, GR ;
ALLEN, JM ;
BACARESEHAMILTON, AJ ;
TATEMOTO, K ;
POLAK, JM ;
BLOOM, SR .
GASTROENTEROLOGY, 1985, 89 (03) :494-499
[3]   Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes [J].
Ahren, Bo .
NATURE REVIEWS DRUG DISCOVERY, 2009, 8 (05) :369-385
[4]  
[Anonymous], 1995, DIABETES, V44, P968
[6]   Biology of incretins: GLP-1 and GIP [J].
Baggio, Laurie L. ;
Drucker, Daniel J. .
GASTROENTEROLOGY, 2007, 132 (06) :2131-2157
[7]   Gut hormone PYY3-36 physiologically inhibits food intake [J].
Batterham, RL ;
Cowley, MA ;
Small, CJ ;
Herzog, H ;
Cohen, MA ;
Dakin, CL ;
Wren, AM ;
Brynes, AE ;
Low, MJ ;
Ghatei, MA ;
Cone, RD ;
Bloom, SR .
NATURE, 2002, 418 (6898) :650-654
[8]   Inhibition of food intake in obese subjects by peptide YY3-36 [J].
Batterham, RL ;
Cohen, MA ;
Ellis, SM ;
Le Roux, CW ;
Withers, DJ ;
Frost, GS ;
Ghatei, MA ;
Bloom, SR .
NEW ENGLAND JOURNAL OF MEDICINE, 2003, 349 (10) :941-948
[9]   GLP-1-induced alterations in the glucose-stimulated insulin secretory dose-response curve [J].
Brandt, A ;
Katschinski, M ;
Arnold, R ;
Polonsky, KS ;
Göke, B ;
Byrne, MM .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 2001, 281 (02) :E242-E247
[10]   The GLP-1 derivative NN2211 restores β-cell sensitivity to glucose in type 2 diabetic patients after a single dose [J].
Chang, AM ;
Jakobsen, G ;
Sturis, J ;
Smith, MJ ;
Bloem, CJ ;
An, B ;
Galecki, A ;
Halter, JB .
DIABETES, 2003, 52 (07) :1786-1791