title: Application of PK/PD modeling and simulation to dosing regimen optimization of high-dose human regular U-500 insulin.
abstract: Pharmacokinetic/pharmacodynamic (PK/PD) studies of human regular U-500 insulin (U-500R) at high doses commonly used in clinical practice (>100 units) have not been performed. The current analysis applied PK/PD modeling/simulation to fit the data and simulate single-dose and steady-state PK/PD of U-500R high-dose regimens. Data from 3 single-dose euglycemic clamp studies in healthy obese and normal-weight patients, and normal-weight patients with type 1 diabetes were used to build the model. The model was sequential (PK inputs fed into PD component). PK was described using a 1-compartment model with first-order absorption and elimination. The model estimated separate absorption rate constants for U-500R and human regular U-100 insulin. The PD component used an effect compartment model, parameterized in terms of maximum pharmacologic effect (E(max)) and concentration to achieve 50% of E(max). The model described the data well. Steady-state PK for once-daily (QD), twice-daily (BID), or thrice-daily (TID) administration appeared to be reached 24 hours after the first dose. At steady-state, QD dosing showed the greatest fluctuations in PK/PD. BID dosing showed a gradual increase in insulin action with each dose and a fairly stable basal insulin effect. For TID dosing, activity was maintained throughout the dosing interval. PK/PD modeling/simulation of high U-500R doses supports BID or TID administration with an extended duration of activity relative to QD. TID dosing may provide slightly better full-day insulin effect. Additional PK/PD studies and randomized controlled trials of U-500R are needed to validate model predictions in patients with insulin-resistant diabetes requiring high-dose insulin.
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA adelapa@lilly.com.
authors.forename: Amparo
authors.initials: A
authors.lastname: de la Peña
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Xiaosu
authors.initials: X
authors.lastname: Ma
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Shobha
authors.initials: S
authors.lastname: Reddy
authors.affiliation: UAB Comprehensive Diabetes Center, Division of Endocrinology, Diabetes & Metabolism, University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Ovalle
authors.affiliation: International Diabetes Center, Park Nicollet Institute, Minneapolis, MN, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Bergenstal
authors.affiliation: Lilly USA, Indianapolis, IN, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Jackson
mesh_terms: D000328:Adult; D000465:Algorithms; D003198:Computer Simulation; D018592:Cross-Over Studies; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007328:Insulin / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D015233:Models, Statistical; D009765:Obesity / Q000378:metabolism; D015203:Reproducibility of Results
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin
keywords: U-500 regular human insulin; dosing; modeling; pharmacodynamics; pharmacokinetics; simulation; time action profile