AIR Inhaled Insulin in Subjects With Chronic Obstructive Pulmonary Disease Pharmacokinetics, glucodynamics, safety, and tolerability KLAUS RAVE, MD 1 AMPARO DE LA PE ˜ NA, PHD 2 FABI ´ AN S. TIBALDI, PHD 3 LIPING ZHANG, PHD 2 BERNARD SILVERMAN, MD 4 MICHAELA HAUSMANN, MD 1 LUTZ HEINEMANN, PHD 1 DOUGLAS B. MUCHMORE, MD 2 OBJECTIVE — In this open-label, randomized, crossover study, pharmacokinetic and glu- codynamic 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 = 15 each)— healthy subjects (baseline mean  SD age 38  13 years, forced expiratory volume in 1 s [FEV 1 ] 4.06  1.04 l), subjects with chronic bronchitis (aged 53  9 years, FEV 1 2.14  0.60 l), and subjects with pulmonary emphysema (aged 58  6 years, FEV 1 1.67  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 admin- istration resulted in reduced insulin exposure (area under the serum insulin concentration curve from time zero until time of return to baseline [AUC 0–t' ]) (55.7%, P = 0.13 and 78.5%, P  0.001, respectively) and reduced total insulin effect (total glucose infusion rate) (60.4%, P  0.01 and 67.1%, P  0.01, respectively) relative to healthy subjects. Subcutaneous insulin lispro administration resulted in similar responses across study groups for insulin exposure and met- abolic effect. Intrasubject pharmacokinetic and glucodynamic variability ranged from 17 to 52% across groups. No significant differences were shown for pre- and postclamp pulmonary func- tion 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, 2007 I nhaled insulin has been approved re- cently 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 ef- fects of inhaled insulin exposure in pa- tients with concomitant lung disease. Similarly, there are little data about how lung disease itself might alter pharmaco- kinetic and glucodynamic responses to inhaled insulin. AIR (a registered trademark of Alk- ermes, Cambridge, MA) is a newly devel- oped inhaled insulin formulation that uses a novel technology to deliver a dry- powder aerosol composed of large, low- density 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 of an inhaler that employs only the energy of a modest inhalation effort to aerosolize the powder. The primary pur- pose of this study was to compare phar- macokinetic and glucodynamic responses, in nonsmoking healthy subjects and non- smoking subjects with moderate chronic obstructive pulmonary disease (COPD), following the administration of either AIR insulin or subcutaneous insulin lispro. Secondary objectives included an evalua- tion of intrasubject variability and pulmo- nary function before and after insulin dosing. RESEARCH DESIGN AND METHODS — A total of 45 subjects, comprised of both healthy subjects and subjects diagnosed with moderate COPD class II (forced expiratory volume in 1 s [FEV 1 ] 30 to 79% of predicted value, re- spectively) (9), were enrolled in this study. Subjects between 18 and 65 years of age, recruited from a number of nearby pulmonology practices, were considered eligible for the screening phase if they pre- sented without a history of diabetes, BMI 35 kg/m 2 , fasting blood glucose 117 mg/dl (6.5 mmol/l), and the ability to per- form spirometry according to American Thoracic Society criteria (10). Subjects with COPD were subcategorized to either a chronic bronchitis group if they had a history of chronic productive cough (pro- ductive cough for at least 3 months in each of the preceding 2 years) or to a pul- monary emphysema group if they lacked ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From the 1 Profil Institute for Metabolic Research fu ¨ r Stoffwechselforschung, Neuss, Germany; 2 Eli Lilly, Indianapolis, Indiana; 3 Eli Lilly Services, Mont-Saint-Guibert, Belgium; and 4 Alkermes, Cambridge, Massa- chusetts. Address correspondence and reprint requests to Dr. Klaus Rave, Profil Institut fu ¨ r Stoffwechselforschung GmbH, Hellersbergstr. 9, 41460 Neuss, Germany. Email: klaus.rave@profil-research.de. Received for publication 1 December 2006 and accepted in revised form 18 April 2007. Published ahead of print at http://care.diabetesjournals.org on 24 April 2007. DOI: 10.2337/dc06-2284. Abbreviations: AUC 0–t' , area under the serum insulin concentration curve from time zero until time of return to baseline; C max , maximum immunoreactive insulin concentration; COPD, chronic obstructive pulmonary disease; DL CO , carbon monoxide diffusing capacity; FEV 1 , forced expiratory volume in 1 s; FVC, forced vital capacity; GIR, glucose infusion rate; IRI, immunoreactive insulin; PFT, pulmonary function test; TLC, total lung capacity. A table elsewhere in this issue shows conventional and Syste `me International (SI) units and conversion factors for many substances. © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Emerging Treatments and Technologies O R I G I N A L A R T I C L E DIABETES CARE, VOLUME 30, NUMBER 7, JULY 2007 1777 Downloaded from http://diabetesjournals.org/care/article-pdf/30/7/1777/597625/zdc00707001777.pdf by guest on 06 July 2022