Evaluation of Drug Efficacy of GLP-1 Receptor Agonists and DPP-4 Inhibitors Based on Target Molecular Binding Occupancy

• Published in: Biological & pharmaceutical bulletin 2018/02/01, Vol.41(2), pp.153-157
• Main Authors: Takayanagi, Risa, Uchida, Takumi, Kimura, Koji, Yamada, Yasuhiko
• Format: Article
• Language: English
• Subjects: Adamantane - administration & dosage; Adamantane - analogs & derivatives; Adamantane - metabolism; Adamantane - pharmacokinetics; Adamantane - therapeutic use; Agonists; Algorithms; Diabetes mellitus; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; dipeptidyl peptidase-4 inhibitor; Dipeptidyl-peptidase IV; Dipeptidyl-Peptidase IV Inhibitors - administration & dosage; Dipeptidyl-Peptidase IV Inhibitors - metabolism; Dipeptidyl-Peptidase IV Inhibitors - pharmacokinetics; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; Dose-Response Relationship, Drug; Drug dosages; Drug Monitoring; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide-1 Receptor - agonists; Glucagon-Like Peptide-1 Receptor - metabolism; glucagon-like peptide-1 receptor agonist; Glycated Hemoglobin A - analysis; Hemoglobin; Humans; Hyperglycemia - prevention & control; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - metabolism; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - therapeutic use; Inhibitors; Ligands; Liraglutide - administration & dosage; Liraglutide - metabolism; Liraglutide - pharmacokinetics; Liraglutide - therapeutic use; Models, Molecular; Molecular Targeted Therapy; Nitric oxide; Nitriles - administration & dosage; Nitriles - metabolism; Nitriles - pharmacokinetics; Nitriles - therapeutic use; Peptidase; Peptides - administration & dosage; Peptides - metabolism; Peptides - pharmacokinetics; Peptides - therapeutic use; pharmacodynamics; pharmacokinetics; Piperidines - administration & dosage; Piperidines - metabolism; Piperidines - pharmacokinetics; Piperidines - therapeutic use; Pyrrolidines - administration & dosage; Pyrrolidines - metabolism; Pyrrolidines - pharmacokinetics; Pyrrolidines - therapeutic use; Reproducibility of Results; Sitagliptin Phosphate - administration & dosage; Sitagliptin Phosphate - metabolism; Sitagliptin Phosphate - pharmacokinetics; Sitagliptin Phosphate - therapeutic use; target molecular binding occupancy; Theoretical analysis; Uracil - administration & dosage; Uracil - analogs & derivatives; Uracil - metabolism; Uracil - pharmacokinetics; Uracil - therapeutic use; Venoms - administration & dosage; Venoms - metabolism; Venoms - pharmacokinetics; Venoms - therapeutic use
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b17-00237

Glucagon-like peptide-1 (GLP-1) receptor agonists (liraglutide, exenatide, lixisenatide) have recently been used as anti-diabetes drugs. We examined relationships of the binding occupancy of GLP-1 receptors (Φ) and their clinical efficacy after administration of GLP-1 receptor agonists. Next, by focusing on changes of GLP-1 concentration after administration of dipeptidyl peptidase-4 (DPP-4) inhibitors (vildagliptin, alogliptin, sitagliptin, linagliptin), we analyzed the relationship between Φ and clinical efficacy. Furthermore, using Φ as a common parameter, we compared the clinical efficacy elicited by GLP-1 receptor agonists and DPP-4 inhibitors using a theoretical analysis method. The present results showed that GLP-1 receptor agonists produced their clinical effect at a relatively low level of Φ (1.1–10.7%) at a usual dose. Furthermore, it was suggested that the drugs might achieve their full effect at an extraordinarily low level of Φ. It was also revealed that the Φ value of DPP-4 inhibitors (0.83–1.3%) was at the lower end or lower than that of GLP-1 receptor agonists at a usual dose. Accordingly, the predicted value for hemoglobin A1c (HbA1c) reduction after administration of the GLP-1 receptor agonists was higher than that of DPP-4 inhibitors. We clarified the differences between the therapeutic effects associated with GLP-1 receptor agonists and DPP-4 inhibitors theoretically. Together, the present findings provide a useful methodology for proper usage of GLP-1 receptor agonists and DPP-4 inhibitors.