Is the Inhibition of Dipeptidyl Peptidase-4 (DDP-4) Enzyme Route Dependent and/or Driven by High Peak Concentration?– Seeking Answers with ZYDPLA1, a Novel Long Acting DPP-4 Inhibitor, in a Rodent Model

Abstract

ZYDPLA1 is a long acting enzyme dipeptidyl peptidase-4 (DPP-4) inhibitor. The comparative effect of DPP-4 inhibition after intravenous (IV) and oral administration of ZYDPLA1 in a rat model was evaluated to answer the question of route dependency and/or the need of high plasma levels of ZYDPLA1. The study was conducted using parallel design in male Wistar rats for IV/oral route (n=9 and 6, for IV and oral respectively). A single 30 mg/kg dose of ZYDPLA1 was administered. Plasma samples were analysed for ZYDPLA1 concentration and DPP-4 inhibition. Pharmacokinetic analysis was carried out to assess peak concentration, area under the concentration–time curve, total body clearance, elimination half-life, and mean residence time. The PK/PD correlation was performed using standard sigmoidal E_max modelling to derive; maximum effect (E_max) and concentration to exert 50% Emax effect (EC₅₀). ZYDPLA1 showed rapid absorption, high volume of distribution, low clearance, and complete oral bioavailability. The E_max derived after both routes and corresponding PK/PD profile showed comparable DDP-4 inhibition. The EC₅₀ for IV (0.021 µg/mL) was comparable to the oral route (0.019 µg/mL). ZYDPLA1 showed full DPP-4 inhibition without regard to the route of administration. Higher systemic peak levels showed no bearing on the DDP-4 inhibition.

Key words

ZYDPLA1 - DPP-4 - Type 2 diabetes mellitus - high performance liquid chromatography tandem mass spectrometry - pharmacokinetics - pharmacodynamics - plasma

• References

• 1 Lipscombe LL. The US diabetes epidemic: tip of the iceberg. Lancet Diabetes Endocrinol 2014; 2: 854-855
• 2 Deacon CF. Therapeutic strategies based on glucagon-like peptide 1. Diabetes 2004; 53: 2181-2189
• 3 Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes, Obesity and Metabolism 2011; 13: 7-18
• 4 Jain MR, Joharapurkar AA, Bahekar RH. et al. Pharmacological characterization of ZYDPLA1, a novel long-acting dipeptidyl peptidase-4 inhibitor. J Diabetes 2015; 7: 708-717
• 5 Reichel A, Lienau P. Pharmacokinetics in drug discovery: an exposure-centred approach to optimising and predicting drug efficacy and safety. Handb Exp Pharmacol 2016; 232: 235-260
• 6 Addy C, Tatosian D, Glasgow XS. et al. Pharmacokinetic and pharmacodynamic effects of multiple-dose administration of omarigliptin, a once-weekly dipeptidyl peptidase-4 inhibitor, in obese participants with and without type 2 diabetes mellitus. Clin Ther 2016; 38: 516-530
• 7 Hansotia T, Baggio LL, Delmeire D. et al. Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors. Diabetes 2004; 53: 1326-1335
• 8 Thomas L, Eckhardt M, Langkopf E. et al. (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methylquinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors. J Pharmacol Exp Ther 2008; 325: 175-182
• 9 Biftu T, Sinha-Roy R, Chen P. et al. Omarigliptin (MK-3102): a novel long-acting DPP‑4 inhibitor for once-weekly treatment of type 2 diabetes. J Med Chem 2014; 57: 3205-3212