Application of PK/PD Modeling and Simulation to Dosing Regimen Optimization of High-Dose Human Regular U-500 Insulin. (July 2014)

• Record Type: Journal Article
• Authors: de la Peña, Amparo; Ma, Xiaosu; Reddy, Shobha; Ovalle, Fernando; Bergenstal, Richard M.; Jackson, Jeffrey A.
• Is Part Of: Journal of diabetes science and technology. Volume 8:Number 4(2014:Jul.)
• Page Start: 821
• Page End: 829
• Publication Date: 2014-07
• Subjects: dosing -- pharmacodynamics -- pharmacokinetics -- modeling -- simulation -- time action profile -- U-500 regular human insulin; Diabetes -- Periodicals; Medical technology -- Periodicals; Diabetes Mellitus -- Periodicals; 616.462005
• DOI: 10.1177/1932296814532326
• Languages: English
• ISSNs: 1932-2968

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 (Emax ) and concentration to achieve 50% of Emax . 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.