Non-linear increase in GLP-1 levels in response to DPP-IV inhibition in healthy adult subjects

• Published in: Diabetes, obesity & metabolism Vol. 10; no. 6; pp. 506 - 513
• Main Authors: Dai, Haiqinq, Gustavson, Stephanie M., Preston, Gregory M., Eskra, James D., Calle, Roberto, Hirshberg, Boaz
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-06-2008
• Subjects: Adult; Cross-Over Studies; Dipeptidyl Peptidase 4 - blood; dipeptidyl peptidase-IV; Dipeptidyl-Peptidase IV Inhibitors - pharmacokinetics; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Fasting; Female; Glucagon-Like Peptide 1 - blood; Glucagon-Like Peptide 1 - drug effects; glucagon-like peptide-1; Humans; Male; Middle Aged; Postprandial Period; Prospective Studies
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/j.1463-1326.2007.00742.x

Aim:  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 Emax 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.
Conclusion:  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.