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.

Keywords: U-500 regular human insulin; dosing; modeling; pharmacodynamics; pharmacokinetics; simulation; time action profile.

Figure 1.

Pharmacokinetic/pharmacodynamic model. PK component: 1-compartment model with first-order absorption and different K_a for U-500R and U-100R, proportional error structure, covariates: dose identified as a significant covariate contributing to interindividual variability of K_a and Clearance; and weight identified as significant for V_d. Sequential model: Pharmacokinetics fixed inputs into pharmacodynamic model. PD component: Effect compartment model with E_max; proportional error structure, covariates: BMI identified as a significant covariate contributing to interindividual variability of E_max. Abbreviations: C_e, concentration in effect compartment; C_s, serum insulin concentration; Ka₁, absorption rate constant for U-100R; Ka₂, absorption rate constant for U-500R; K₂₀, elimination rate constant from the central (serum) compartment; K₂₃ and K₃₂, distribution rate constants between the serum and effect compartments; SC, subcutaneous.

Figure 2.

Pharmacokinetic/pharmacodynamic model goodness of fit for U-500R and U-100R, 50 U and 100 U doses. The orange line and shaded area represent the model-estimated median and 90th prediction interval respectively; the solid circles represent individual data points.

Figure 3.

Pharmacokinetic/pharmacodynamic modeling of single (QD) daily doses of U-500R: 165 U, 250 U, 500 U, 750 U. The hatched area represents the 90th prediction interval from the model; the thicker line represents the median.

Figure 4.

Pharmacokinetic/pharmacodynamic modeling of U-500R doses at steady-state: 500 U QD, 250 U BID, 165 U TID. QD doses were administered at 7 am, BID doses at 7 am and 6 pm, and TID doses at 7 am, 12 noon, and 6 pm. The hatched area represents the 90th prediction interval from the model; the thicker line represents the median.

Figure 5.

Pharmacokinetic/pharmacodynamic modeling of U-500R doses at steady-state during 24 hours of Day 5: 500 U QD, 250 U BID, 165 U TID. Arrows represent dose administration times: for QD at 7 am, BID at 7 am and 6 pm, and TID at 7 am, 12 noon, and 6 pm.

Figure 6.

Pharmacokinetic/pharmacodynamic modeling of U-500R insulin at steady state: varied proportion dosing (BID doses at 7 am and 6 pm, and TID doses at 7 am, 12 noon, and 6 pm).