title: Pharmacokinetics and pharmacodynamics of high-dose human regular U-500 insulin versus human regular U-100 insulin in healthy obese subjects.
abstract: 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).
  
  
  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 [AUC(0-)(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 tR(max50), tR(last)) 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.
authors: Eli Lilly and Company, Indianapolis, Indiana, USA. de_la_pena_amparo@lilly.com
authors: Amparo
authors: A
authors: de la Peña
authors: Matthew
authors: M
authors: Riddle
authors: Linda A
authors: LA
authors: Morrow
authors: Honghua H
authors: HH
authors: Jiang
authors: Helle
authors: H
authors: Linnebjerg
authors: Adam
authors: A
authors: Scott
authors: Khin M
authors: KM
authors: Win
authors: Marcus
authors: M
authors: Hompesch
authors: Kenneth F
authors: KF
authors: Mace
authors: Jennie G
authors: JG
authors: Jacobson
authors: Jeffrey A
authors: JA
authors: Jackson
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001786:Blood Glucose / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D061386:Insulin, Regular, Human / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000188:drug therapy*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D061386:Insulin, Regular, Human