Pharmacokinetic–pharmacodynamic (dipeptidyl peptidase‐4 inhibition) model to support dose rationale in diabetes patients, including those with renal impairment, for once‐weekly administered omarigliptin

• Published in: British journal of clinical pharmacology Vol. 85; no. 12; pp. 2759 - 2771
• Main Authors: Jain, Lokesh, Chain, Anne S.Y., Tatosian, Daniel A., Hing, Jeremy, Passarell, Julie A., Kauh, Eunkyung A., Lai, Eseng
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.12.2019
• Subjects: Blood Glucose - analysis; Clinical Trials as Topic; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Dipeptidyl Peptidase 4 - blood; dipeptidyl peptidase‐4 inhibitor; Dipeptidyl-Peptidase IV Inhibitors - administration & dosage; Dipeptidyl-Peptidase IV Inhibitors - blood; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; Dose-Response Relationship, Drug; Drug Administration Schedule; Heterocyclic Compounds, 2-Ring - administration & dosage; Heterocyclic Compounds, 2-Ring - blood; Heterocyclic Compounds, 2-Ring - therapeutic use; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - blood; Hypoglycemic Agents - therapeutic use; Kidney Failure, Chronic - blood; Kidney Failure, Chronic - complications; Kidney Failure, Chronic - drug therapy; Models, Biological; omarigliptin; Original; population pharmacodynamics; population pharmacokinetics; Pyrans - administration & dosage; Pyrans - blood; Pyrans - therapeutic use; Renal Insufficiency - blood; Renal Insufficiency - complications; Renal Insufficiency - drug therapy; type 2 diabetes mellitus; type 2 diabetes mellitus; dipeptidyl peptidase-4 inhibitor; population pharmacodynamics; omarigliptin; population pharmacokinetics
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.14103

Aims To characterize the population pharmacokinetics (PK) and pharmacodynamics (PD) of the once‐weekly dipeptidyl peptidase‐4 (DPP‐4) inhibitor omarigliptin in healthy subjects and patients with type 2 diabetes mellitus, and use these models to support the dosing recommendation for patient labelling including patients with renal impairment. Methods PK and PD were assessed from a total of 9827 omarigliptin concentrations collected from 1387 healthy subjects and patients participating in Phase 1, 2 and 3 studies examining single‐ or multiple‐dose weekly administration of omarigliptin at doses ranging from 0.25 to 400 mg. Population PK and PD analyses were performed using nonlinear mixed effect modelling. Results A semi‐mechanistic 2‐compartment model with linear unbound clearance and concentration‐dependent binding of omarigliptin to the DPP‐4 enzyme in both the central and peripheral compartments adequately described omarigliptin PK. Key covariates on omarigliptin PK included reduced unbound clearance with renal impairment. A direct effect sigmoid maximum inhibitory efficacy model adequately described the relationship between omarigliptin plasma concentrations and DPP‐4 inhibition. These models supported the current Japan label instructions that the approved omarigliptin 25‐mg once‐weekly dose be halved in patients with severe renal impairment and in those with end‐stage renal disease. Also, if patients missed a dose, the next dose of omarigliptin should be taken as soon as remembered up to and including the day before the next scheduled dose. No other clinically important covariates were identified. Conclusion The models in the present analysis adequately described PK and PD characteristics of omarigliptin and supported the dosing and administration section of the omarigliptin label.