title: Pulmonary insulin administration using the AERx system: physiological and physicochemical factors influencing insulin effectiveness in healthy fasting subjects.
abstract: BACKGROUND
  Orally inhaled insulin may provide a convenient and effective therapy for prandial glucose control in patients with diabetes. This study evaluated the influence of formulation pH and concentration and different respiratory maneuvers on pharmacokinetic and pharmacodynamic properties of inhaled insulin.
  
  
  METHODS
  Three, open-label crossover studies in a total of 23 healthy subjects were conducted in which the safety, pharmacokinetics, and pharmacodynamics of insulin inhalation were compared to subcutaneous (SC) injection into the abdomen of commercially available regular insulin. A novel, aerosol generating system (AERx Diabetes Management System, Aradigm Corporation, Hayward, CA) was used to deliver aqueous insulin bolus aerosols to the lower respiratory tract from formulations at pH 3.5 or 7.4 and concentrations of U250 (250 U/mL) or U500 (500 U/mL).
  
  
  RESULTS
  Time to maximum insulin concentration in serum (Tmax) after SC dosing occurred approximately 50-60 minutes with the time to minimum plasma glucose concentration (i.e., maximum hypoglycemic effect), (TGmin), occurring later, at around 100-120 minutes. In contrast, pulmonary delivery led to a significantly earlier Tmax (7-20 minutes) and TGmin (60-70 minutes), parameters that were shown to be largely unaffected by changing the pH or concentration of the insulin. However, investigation of changes in inhaled volume (achieved by different programming of the AERx system) for administration of the same sized aerosol bolus revealed significant effects. Significantly slower absorption and time to peak hypoglycemic activity occurred when aerosol delivery of insulin occurred during a shallow (approximately 40% vital capacity) as opposed to a deep (approximately 80% vital capacity) inspiration. In addition, it was shown that serum concentration of insulin increased immediately after a series of forced expiraratory maneuvers 30 minutes after inhaled delivery.
  
  
  CONCLUSIONS
  Pulmonary delivery of aqueous bolus aerosols of insulin in healthy subjects resulted in rapid absorption with an associated hypoglycemic effect quicker than is achieved after subcutaneous dosing of regular insulin. Inhaled insulin pharmacokinetics and pharmacodynamics were independent of formulation variables (pH, concentration) but affected by certain respiratory maneuvers.
authors.affiliation: Aradigm Corporation, Hayward, California 94545, USA. farrs@aradigm.com
authors.forename: S J
authors.initials: SJ
authors.lastname: Farr
authors.forename: A
authors.initials: A
authors.lastname: McElduff
authors.forename: L E
authors.initials: LE
authors.lastname: Mather
authors.forename: J
authors.initials: J
authors.lastname: Okikawa
authors.forename: M E
authors.initials: ME
authors.lastname: Ward
authors.forename: I
authors.initials: I
authors.lastname: Gonda
authors.forename: V
authors.initials: V
authors.lastname: Licko
authors.forename: R M
authors.initials: RM
authors.lastname: Rubsamen
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000336:Aerosols; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D018592:Cross-Over Studies; D005215:Fasting; D006801:Humans; D007279:Injections, Subcutaneous; D007328:Insulin / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology*; D008297:Male; D012016:Reference Values; D012449:Safety; D013997:Time Factors
chemical_list: D000336:Aerosols; D001786:Blood Glucose; D007328:Insulin