Pharmacologic Response and Safety of Inhaled Insulin in Type 1 Diabetes

This first-in-human trial investigated the optimal particle size for absorption of Dance-501, an aerosolized liquid human insulin for inhalation (INH).

Twelve subjects with type 1 diabetes received an INH dose (50 IU) using an inhaler on 4 visits and 6 U insulin lispro (LIS) sc on a separate visit to assess relative bioavailability (FREL) of INH. The inhaler was configured to generate insulin aerosol particles sized 3.5-4.0 μm (low output mesh; LOM), 4.3-4.8 μm (medium output mesh; MOM) or 5.0-5.5 μm (high output mesh; HOM) during low inspiratory flow. To assess within subject variability, MOM was used twice. Pharmacokinetics (PK) were measured up to 8 hours after dosing.

Inclusion criteria

• Type 1 diabetes mellitus treated with multiple daily insulin injections or continuous subcutaneous insulin infusion and total daily insulin dose less than 1.2 units/kg/day.
• Body mass index 18.0 - 28.0 kg/m2.
• Hemoglobin A1c less than or equal to 9%.
• Forced vital capacity and forced expiratory volume in one second at least 75% of predicted normal values for race, age, gender and height.
• Fasting C-peptide less than 0.3 nmol/L.

Exclusion criteria

• Subjects with any condition possibly affecting drug absorption from the lung, in particular subjects with decreased lung function or subjects taking bronchodilators or subjects who smoke.
• Active or chronic pulmonary disease.
• Any clinically significant major disorders other than diabetes mellitus.
• Decompensated heart failure at any time or angina pectoris within the last 12 months or acute myocardial infarction at any time.
• Proliferative retinopathy or severe neuropathy.