Pharmacokinetics and Pharmacodynamics of High-Dose Human Regular U-500 Insulin Versus Human Regular U-100 Insulin in Healthy Obese Subjects

• DOI: 10.2337/dc11-0721
• Publication Date: 2011-10-14T01:00:17Z
• Authors: Amparo de la Peña; Matthew Riddle; Linda A. Morrow; Honghua H. Jiang; Helle Linnebjerg; Adam Scott; Khin M. Win; Marcus Hompesch; Kenneth F. Mace; Jennie G. Jacobson; Jeffrey A. Jackson
• Keywords: Adult; Blood Glucose; Male; 2. Zero hunger; Cross-Over Studies; Middle Aged; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Double-Blind Method; Area Under Curve; Insulin, Regular, Human; Glucose Clamp Technique; Humans; Hypoglycemic Agents; Female; Obesity; Original Research; Aged

OBJECTIVE Human regular U-500 (U-500R) insulin (500 units/mL) is increasingly being used clinically, yet its pharmacokinetics (PK) and pharmacodynamics (PD) have not been well studied. Therefore, we compared PK and PD of clinically relevant doses of U-500R with the same doses of human regular U-100 (U-100R) insulin (100 units/mL).

RESEARCH DESIGN AND METHODS This was a single-site, randomized, double-blind, crossover euglycemic clamp study. Single subcutaneous injections of 50- and 100-unit doses of U-500R and U-100R were administered to 24 healthy obese subjects.

RESULTS Both overall insulin exposure (area under the serum insulin concentration versus time curve from zero to return to baseline [AUC0-t’]) and overall effect (total glucose infused during a clamp) were similar between formulations at both 50- and 100-unit doses (90% [CI] of ratios contained within [0.80, 1.25]). However, peak concentration and effect were significantly lower for U-500R at both doses (P < 0.05). Both formulations produced relatively long durations of action (18.3 to 21.5 h). Time-to-peak concentration and time to maximum effect were significantly longer for U-500R than U-100R at the 100-unit dose (P < 0.05). Time variables reflective of duration of action (late tRmax50, tRlast) were prolonged for U-500R versus U-100R at both doses (P < 0.05).

CONCLUSIONS Overall exposure to and action of U-500R insulin after subcutaneous injection were no different from those of U-100R insulin. For U-500R, peaks of concentration and action profiles were blunted and the effect after the peak was prolonged. These findings may help guide therapy with U-500R insulin for highly insulin-resistant patients with diabetes.