title: Inhaled micronized crystalline human insulin using a dry powder inhaler: dose-response and time-action profiles.
abstract: OBJECTIVE
  The aim of this euglycaemic glucose clamp study was to investigate the pharmacokinetics, glucodynamics, safety and tolerability of micronized crystalline human insulin inhalation powder delivered by a Spiros dry powder inhaler system in healthy volunteers.
  
  
  METHODS
  Thirteen healthy, non-smoking, male and female volunteers [age 30 +/- 7 years; BMI 23.5 +/- 2.7 kg/m(2); (mean +/- sd)] with normal pulmonary function participated in an open-label, randomised, 6-period crossover trial. Each volunteer received four single doses of inhaled insulin (60, 90, 120, 150 U) on separate occasions. For comparison, each volunteer also received two of three possible doses of subcutaneous (s.c.) injected regular human insulin (8, 14, or 20 U).
  
  
  RESULTS
  Serum immunoreactive insulin following inhalation of insulin peaked an average of 60 min earlier compared with s.c. injected insulin (P < 0.0001). Following inhalation, the time to maximum glucose infusion rate occurred an average of 70 min earlier than with s.c. insulin: 187, 129, 161 and 162 min vs. 227, 241 and 241 min (P < 0.0001). The dose-response relationships for serum insulin pharmacokinetics and glucodynamics were linear for both inhaled and s.c. insulin. Relative bioavailability (based on serum insulin levels) ranged from 11.5 to 12.2% for the four doses of inhaled insulin and relative biopotency (based on glucose infusion rates) was 10.0 to 16.5%, respectively. Dosing was well tolerated by all volunteers.
  
  
  CONCLUSIONS
  This study demonstrates that inhalation of human insulin via a dry powder inhaler system provides a promising alternative route for administration of insulin.
authors.affiliation: Profil Institute for Metabolic Research, Hellersbergstrasse 9, D-41460 Neuss, Germany. klaus.rave@profil-research.de
authors.forename: K
authors.initials: K
authors.lastname: Rave
authors.forename: L
authors.initials: L
authors.lastname: Nosek
authors.forename: L
authors.initials: L
authors.lastname: Heinemann
authors.forename: C
authors.initials: C
authors.lastname: Gonzales
authors.forename: C S
authors.initials: CS
authors.lastname: Ernest
authors.forename: J
authors.initials: J
authors.lastname: Chien
authors.forename: D
authors.initials: D
authors.lastname: Muchmore
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D001682:Biological Availability; D018592:Cross-Over Studies; D003460:Crystallization; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000097:blood; D007279:Injections, Subcutaneous; D007328:Insulin / Q000008:administration & dosage* / Q000097:blood; D008297:Male; D036501:Metered Dose Inhalers
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin