title: A comparison of the steady-state pharmacokinetic and pharmacodynamic profiles of 100 and 200 U/mL formulations of ultra-long-acting insulin degludec.
abstract: OBJECTIVE
  Insulin degludec (IDeg) is a new-generation basal insulin that forms soluble multi-hexamers upon subcutaneous injection, resulting in a depot from which IDeg monomers are slowly and continuously absorbed to provide an ultra-long action profile. This double-blind, crossover, randomized study compared the pharmacokinetic and pharmacodynamic properties between IDeg 100 U/mL (U100) and IDeg 200 U/mL (U200) under steady-state (SS) conditions in subjects with type 1 diabetes mellitus.
  
  
  METHODS
  Participants (n = 33 adults) underwent 8-day treatment periods with 0.4 U/kg IDeg U100 and IDeg U200 given once daily with insulin aspart at mealtimes. On day 8, a 26-h euglycaemic glucose clamp (5.5 mmol/L) was performed.
  
  
  RESULTS
  The concentration-time profiles of IDeg U100 and IDeg U200 were similar, and a post-hoc analysis showed bioequivalence between these formulations, as the 90 % confidence intervals (CIs) of the U200/U100 ratios for area under the steady-state serum IDeg concentration-time curve during a dosing interval (τ; 0-24 h) (AUCτ,SS,IDeg) (0.99 [0.91-1.07]) and maximum steady-state IDeg concentration during a dosing interval (τ) (C max,SS,IDeg) (0.93 [0.84-1.02]) were within the interval 0.80-1.25. Comparable glucose infusion rates (GIR) were observed for IDeg U100 and IDeg U200 (AUCτ,SS,GIR [mg/kg]: 2,255 vs. 2,123) and the mean ratio (95 % CI) of IDeg U200/U100 for the primary endpoint (AUCτ,SS,GIR) was 0.94 [0.86-1.03]. For both formulations, the glucose-lowering effect of IDeg was evenly distributed between the first and second 12 h post-dosing (U100: AUC12,SS,GIR/AUC24,SS,GIR = 48 %; U200: AUC12,SS,GIR/AUC24,SS,GIR = 46 %). Both formulations were well tolerated, and no safety events of significance were identified.
  
  
  CONCLUSIONS
  IDeg U100 and U200 formulations are bioequivalent and have similar pharmacodynamic profiles at SS, implying that they can be used interchangeably in clinical practice.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University Graz, Auenbruggerplatz 15, 8036, Graz, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Korsatko
authors.forename: Sigrid
authors.initials: S
authors.lastname: Deller
authors.forename: Gerd
authors.initials: G
authors.lastname: Koehler
authors.forename: Julia K
authors.initials: JK
authors.lastname: Mader
authors.forename: Katharina
authors.initials: K
authors.lastname: Neubauer
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Adrian
authors.forename: Henrik
authors.initials: H
authors.lastname: Thomsen
authors.forename: Hanne
authors.initials: H
authors.lastname: Haahr
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Pieber
mesh_terms: D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D049528:Insulin, Long-Acting / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008875:Middle Aged
chemical_list: D049528:Insulin, Long-Acting; C571886:insulin degludec