AIR Inhaled Insulin in Subjects With Chronic Obstructive Pulmonary Disease

Abstract

OBJECTIVE -In this open-label, randomized, crossover study, pharmacokinetic and glucodynamic responses were compared in healthy subjects versus subjects with moderate chronic obstructive pulmonary disease (COPD), following administration of 12 units equivalent AIR inhaled insulin versus 12 units subcutaneous insulin lispro.RESEARCH DESIGN AND METHODS -Three nonsmoking groups (n ϭ 15 each)-healthy subjects (baseline mean Ϯ SD age 38 Ϯ 13 years, forced expiratory volume in 1 s [FEV 1 ] 4.06 Ϯ 1.04 l), subjects with chronic bronchitis (aged 53 Ϯ 9 years, FEV 1 2.14 Ϯ 0.60 l), and subjects with pulmonary emphysema (aged 58 Ϯ 6 years, FEV 1 1.67 Ϯ 0.61 l)-were randomly assigned to one of three treatment sequences. Three euglycemic glucose clamp procedures were performed.RESULTS -In subjects with chronic bronchitis and emphysema, AIR inhaled insulin administration resulted in reduced insulin exposure (area under the serum insulin concentration curve from time zero until time of return to baseline [AUC 0 -tЈ ]) (55.7%, P ϭ 0.13 and 78.5%, P Ͻ 0.001, respectively) and reduced total insulin effect (total glucose infusion rate) (60.4%, P Ͻ 0.01 and 67.1%, P Ͻ 0.01, respectively) relative to healthy subjects. Subcutaneous insulin lispro administration resulted in similar responses across study groups for insulin exposure and metabolic effect. Intrasubject pharmacokinetic and glucodynamic variability ranged from 17 to 52% across groups. No significant differences were shown for pre-and postclamp pulmonary function tests. During clamps, FEV 1 and forced vital capacity declined modestly in both COPD groups, with no difference between AIR insulin and subcutaneous insulin lispro.CONCLUSIONS -Short-term exposure to AIR inhaled insulin was well tolerated by COPD subjects, showing similar time-exposure and time-action profiles, but with reduced insulin absorption and metabolic effect compared with healthy subjects. Further clinical evaluation is warranted in patients with comorbid diabetes and COPD. Diabetes Care 30:1777-1782, 2007I nhaled insulin has been approved recently in both Europe and the U.S. as an alternative to subcutaneous insulin injection in the treatment of patients with diabetes. A number of clinical trials in subjects with diabetes have demonstrated the feasibility and patient acceptance of administering insulin by the pulmonary route (1-6); however, there is little or no information on the acute or chronic effects of inhaled insulin exposure in patients with concomitant lung disease. Similarly, there are little data about how lung disease itself might alter pharmacokinetic and glucodynamic responses to inhaled insulin.AIR (a registered trademark of Alkermes, Cambridge, MA) is a newly developed inhaled insulin formulation that uses a novel technology to deliver a drypowder aerosol composed of large, lowdensity particles (2-5 m in aerodynamic diameter) of spray-dried human insulin in an excipient matrix (7). This type of formulation results in a high dispersibility of respirable particles (8) and allows for the use...

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“…Over the first 180 min post-dose, Exubera s delivered less than half of its total glucose-lowering activity. The duration of glucose-lowering activity for Exubera s was approximately 6.5 h. The time-action profile for 12 U of AIR s was similar, with a time to maximal glucose-lowering activity of 261 min and a broad peak of glucoselowering activity over more than 6 h [Rave et al, 2007a]. The protracted glucose-lowering activity of AIR s may explain the statistically significantly increased rate of nocturnal hypoglycemia observed in patients with type 1 diabetes treated with AIR s vs. s.c. insulin lispro [Garg et al, 2006].…”

“…The maximal serum insulin levels were comparable between the two treatments (66.9 mU/ml for Exubera s , 61.0 mU/ml for s.c. RHI). In a study of healthy subjects, the t max for 12 U of AIR s was 45 min with a C max of 44 mU/ml; 12 U of AIR s was considered equivalent to 12 U of s.c. insulin lispro [Rave et al, 2007a].…”

Novel Hormonal Delivery Method Using the Ink-Jet Technology: Application to Pulmonary Insulin Therapies

“…23,24 Insulin action was impaired among patients over 65 years old or slightly impaired among bronchial asthma patients 22,25 and was enhanced or impaired among patients with chronic obstructive pulmonary disease. 26 Patients with chronic obstructive pulmonary disease demonstrated a variable absorption of insulin compared with subjects without this disorder. It is not clear whether this variability is secondary to differences in inhalation devices or to differences in study populations.…”

Intestinal Receptor Targeting for Peptide Delivery: an expert‘s Personal Perspective on Reasons for Failure and New Opportunities

“…There are several pulmonary delivery systems for insulin that have been developed including Exubera ® (Pfizer), AERx ® iDMS (Aradigm, USA), AIR (Alkermes, USA), Technosphere ® (MannKind Corp, USA) and AERODOSE ® (AeroGen Inc, USA) [173,[193][194][195][196][197][198]. However, no mechanism has been proposed to explain uptake via this route.…”