title: Dose response of inhaled dry-powder insulin and dose equivalence to subcutaneous insulin lispro.
abstract: OBJECTIVE
  To determine the pharmacokinetic (PK) and glucodynamic (GD) dose response of human insulin inhalation powder (HIIP) delivered via AIR particle technology and dose equivalence to subcutaneous (SC) insulin lispro.
  
  
  METHODS
  Twenty healthy, nonsmoking, male or female subjects (aged 29.6 +/- 6.9 years, BMI 23.2 +/- 2.3 kg/m2, means +/- SD) with normal forced vital capacity and forced expiratory volume were enrolled in an open-label, randomized, seven-period, euglycemic glucose clamp, cross-over trial. Each subject received up to four single doses of HIIP (2.6, 3.6, 5.2, or 7.8 mg) and three doses of SC lispro (6, 12, or 18 units) from 5 to 18 days apart.
  
  
  RESULTS
  HIIP demonstrated a similar rapid onset but an extended time exposure and a prolonged duration of effect (late t(50%) 412 vs. 236 min, P < 0.001) compared with SC lispro. The HIIP versus SC lispro doses of 2.6 mg vs. 6 units, 5.2 mg vs. 12 units, and 7.8 mg vs. 18 units achieved similar PK area under the serum immunoreactive insulin (IRI) concentration-versus-time curve from time zero until the serum IRI concentrations returned to the predose baseline value [AUC(0-t')] and GD (G(tot)) responses. The median insulin (t(max)) was not different between HIIP and SC lispro (45 min for both), although the median time of return to baseline for PK was apparently longer for HIIP compared with SC lispro (480 vs. 360 min). Relative bioavailability and relative biopotency of HIIP were consistent across doses (8 and 9%).
  
  
  CONCLUSIONS
  While the time-action profile was longer for HIIP than for SC lispro, both treatments showed rapid initial absorption and similar overall PK exposure and GD effect. HIIP was as well tolerated as SC lispro, thereby offering a promising alternative to injectable insulin therapy.
authors.affiliation: Profil Institut für Stoffwechselforschung, Hellersbergstr. 9, D-41460 Neuss, Germany. klaus.rave@profil-research.de
authors.forename: Klaus M
authors.initials: KM
authors.lastname: Rave
authors.forename: Leszek
authors.initials: L
authors.lastname: Nosek
authors.forename: Amparo
authors.initials: A
authors.lastname: de la Peña
authors.forename: Mary
authors.initials: M
authors.lastname: Seger
authors.forename: Charles S
authors.initials: CS
authors.lastname: Ernest
authors.forename: Lutz
authors.initials: L
authors.lastname: Heinemann
authors.forename: Richard P
authors.initials: RP
authors.lastname: Batycky
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Muchmore
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007279:Injections, Subcutaneous; D007328:Insulin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D061268:Insulin Lispro; D008297:Male; D036501:Metered Dose Inhalers; D011208:Powders; D016896:Treatment Outcome
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D061268:Insulin Lispro; D011208:Powders