Insulin pharmacokinetics following dosing with Technosphere insulin in subjects with chronic obstructive pulmonary disease

Abstract

Objectives:

Insulin exposure after inhalation has been reported to be altered significantly in subjects with chronic obstructive pulmonary disease (COPD). In this study, the rate and extent of insulin exposure was compared in healthy volunteers and subjects with COPD following administration of Technosphere Insulin (TI), a dry powder insulin formulation for pulmonary delivery.

Methods:

Insulin pharmacokinetics were evaluated in an open-label, single-dose, hyperinsulinemic-euglycemic glucose clamp study in 19 nondiabetic, nonsmoking healthy subjects (mean age [±SD] = 50.9 ± 14.1 years, body mass index = 29.1 ± 3.5 kg/m², forced expiratory volume in 1 second (FEV₁) = 3.52 ± 1.02 L) and 17 nondiabetic subjects with mild-to-moderate COPD (mean age = 60.0 ± 9.0 years, body mass index = 28.5 ± 5 kg/m², FEV₁ = 2.56 ± 0.83 L). Subjects received a single 30-U dose of TI. Serial blood samples were obtained for insulin and C-peptide determination through 480 min after dosing. Insulin concentrations were adjusted for endogenous insulin by C-peptide correction; pharmacokinetic parameters were estimated using the corrected values.

Results:

For the COPD and non-COPD groups, respectively, mean peak insulin (C_max) was 34.7 µU/mL and 39.5 µU/mL (p = 0.29), median t_max was 15 and 12 min (p = 0.24), and mean insulin exposure from time 0 to 240 min (AUC_0–240) was 2037 µU/mL · min and 2279 µU/mL · min (p = 0.47). Cough was the most common respiratory adverse event observed. One instance of hypoglycemia was reported and was attributed to trial procedure.

Conclusions:

The rapid insulin absorption and the resulting insulin pharmacokinetic profile following TI inhalation were not significantly altered in the mild-to-moderate COPD population studied; however, long-term safety and efficacy of TI have not been established in patients with mild or moderate COPD. Longer-term experience is needed to fully characterize the effects of COPD on insulin PK following TI administration.

Key words:

• COPD
• Inhaled insulin
• Pharmacokinetics
• Technosphere Insulin

Transparency

Declaration of funding

This study was funded by MannKind Corporation, Valencia, CA, USA. MannKind Corporation participated in the study design; the collection, analysis, and interpretation of data; the writing of the report; and the decision to submit the report for publication.

Declaration of financial/other relationships

E.P., R.B., J.C., N.A., and P.R. are employees of MannKind Corporation. S.S. served as a principal investigator for this study. At the time of writing, M.G. was an employee of MannKind Corporation.

Peer reviewers may receive honoraria from CMRO for their review work. The peer reviewers have disclosed no relevant financial relationships.

Acknowledgments

The authors thank principal investigators Jeroen van de Wetering de Rooij, MD, PRA International Group BV, Groningen, The Netherlands; Cyril Clarke, MD, ICON Development Solutions, Manchester, UK; and Dave Singh, MD, Medicines Evaluation Unit Ltd, Manchester, UK. We also thank Mark Marino, MD, MannKind Corporation, for support with the C-peptide correction calculations and Thomas J. Greene, MD, MannKind Corporation, for providing assistance with this manuscript.

The data were previously presented at the European Association for the Study of Diabetes annual meeting, Vienna, Austria, September 29 to October 2, 2009, and at the American Diabetes Association annual meeting, New Orleans, LA, June 5–9, 2009.

Notes

*MannKind Corporation, Valencia, CA, USA.

†Technosphere is a registered trademark of MannKind Corporation, Valencia, CA, USA.

*Exubera is a registered trademark of Pfizer Inc, New York, NY, USA.

†AIR is a registered trademark of Alkermes, Cambridge, USA.