Although the pharmacokinetics and pharmacodynamics of high-dose human regular U-500 and human regular U-100 insulin are similar, the U-500 formulation may have a longer duration of action.…
The use of regular U-500 insulin (U-500R) (500 units/mL) is rising in the face of increasing numbers of patients requiring high insulin doses, but PK/PD data for the higher doses of U-500R typically used in clinical practice are scarce.
Dr. Amparo de la Pena from Eli Lilly and Company in Indianapolis and colleagues evaluated the relative exposure after two clinically relevant doses (50 units and 100 units) of U-500R versus U-100 human regular insulin (U-100R) (100 units/mL) in a crossover study of 24 healthy obese subjects. Overall insulin exposure based on AUC(0-t) was similar between U-500R and U-100R formulations at both doses.
At both doses, the maximum concentration of insulin achieved (Cmax) was significantly lower for U-500R (50 units: 548 pmol/L; 100 units: 1,020 pmol/L) than for U-100R (50 units: 809 pmol/L; 100 units: 1,400 pmol/L) (p<0.05).
For the 100-unit dose, the time of maximum concentration (Tmax) was significantly longer for U-500R than for U-100R (8 hours vs. 3 hours, p<0.05). There was no significant difference in Tmax for the lower dose.
As expected from these PK data, time variables reflective of duration of action were prolonged for U-500R versus U-100R at both doses, although the time of onset was similar for both doses of both formulations. At the 100-unit dose, the duration of action was 18.3 hours for U-100R and 21.5 hours for U-500R (p<0.05).
The investigators noted that the findings have potential clinical implications. “For example, the delayed time-to-peak and prolonged total duration of action of high-dose U-100R suggests the commonly used 50:50 distribution of basal to prandial components of a basal-bolus regimen may not be appropriate at high dosage. If U-500R is used instead of U-100R, the longer duration of action of U-500R may support its use as multiple daily injections without the use of a basal insulin.”
“Confirmation of the present findings, particularly the lack of improved absorption/bioavailability of U-500R versus U-100R in very obese patients with type 2 diabetes would be of interest,” they add. “Further study with randomized clinical trials is needed to determine the optimal therapeutic application, safety, and efficacy of concentrated U-500R insulin.”