title: AIR insulin capsules of different dose strengths may be combined to yield equivalent pharmacokinetics and glucodynamics.
abstract: BACKGROUND
  In order to assess pharmacokinetic (PK) and glucodynamic (GD) attributes relevant to the end user of an inhaled insulin, this study examined the exposure and GD effect of doses of AIR inhaled insulin (Eli Lilly and Co., Indianapolis, IN) (AIR is a registered trademark of Alkermes, Inc., Cambridge, MA) by combining capsules of different strengths in healthy subjects.
  
  
  METHODS
  Fifty-nine healthy, nonsmoking, male or female subjects with normal pulmonary function were enrolled in an open-label, randomized, crossover study. Subjects underwent up to five euglycemic glucose clamp procedures, separated by 5-18 days. The five AIR insulin treatments tested included one 6 unit-equivalent (U-eq) capsule containing 2.6 mg of insulin, three 2 U-eq (0.9 mg) capsules (2.7 mg total), one 10 U-eq (3.9 mg) capsule, one 6 U-eq capsule plus two 2 U-eq capsules (4.4 mg total), and two 10 U-eq capsules (7.8 mg total). Samples for PK and GD assessments were taken up to 10 h post-dose.
  
  
  RESULTS
  Based on both PK (area under the curve from time 0 to time of return to baseline and maximum concentration) and GD (total amount of glucose infused and maximum glucose infusion rate) responses, administration of a 6 U-eq capsule was equivalent to three 2 U-eq capsules; 90% confidence intervals for the ratios were contained within the interval (0.8, 1.25). Similarly, both overall exposure and glucodynamic response after administration of a 10 U-eq capsule were comparable to the 6 U-eq plus two 2 U-eq capsule combination. AIR insulin exhibited PK dose proportionality and dose-dependent increases in GD responses over the 2.6-7.8 mg dose range.
  
  
  CONCLUSIONS
  AIR insulin exhibited dose strength interchangeability and dose proportionality after single-dose administration in healthy subjects.
authors.affiliation: Eli Lilly and Company, Indianapolis, Indiana 46285, USA. adelapa@lilly.com
authors.forename: Amparo
authors.initials: A
authors.lastname: de la Peña
authors.forename: Mary
authors.initials: M
authors.lastname: Seger
authors.forename: Klaus
authors.initials: K
authors.lastname: Rave
authors.forename: Lutz
authors.initials: L
authors.lastname: Heinemann
authors.forename: Bernard
authors.initials: B
authors.lastname: Silverman
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Muchmore
mesh_terms: D000280:Administration, Inhalation; D019540:Area Under Curve; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D018592:Cross-Over Studies; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D012016:Reference Values; D014797:Vital Capacity / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin