AIR inhaled insulin versus subcutaneous insulin: pharmacokinetics, glucodynamics, and pulmonary function in asthma.

OBJECTIVE: This study evaluated pharmacokinetic and glucodynamic responses to AIR inhaled insulin relative to subcutaneous insulin lispro, safety, pulmonary function, and effects of salbutamol coadministration. RESEARCH DESIGN AND METHODS: Healthy, mildly asthmatic, and moderately asthmatic subjects (n = 13/group, aged 19-58 years, nonsmoking, and nondiabetic) completed this phase I, open-label, randomized, crossover euglycemic clamp study. Subjects received 12 units equivalent AIR insulin or 12 units subcutaneous insulin lispro or salbutamol plus AIR insulin (moderate asthma group only) before the clamp. RESULTS: AIR insulin exposure was reduced 34 and 41% (both P < 0.01) in asthmatic subjects (area under the curve(0-t'), 24.0 and 21.1 nmol x min x l(-1) in mild and moderate asthma subjects, respectively) compared with healthy subjects (35.2 nmol x min x l(-1)), respectively. Glucodynamic (G) effects were similar in healthy and mildly asthmatic subjects (G(tot) = 38.7 and 23.4 g, respectively; P = 0.16) and were reduced in moderately asthmatic subjects (G(tot) = 10.7 g). Salbutamol pretreatment (moderately asthmatic subjects) improved bioavailability. AIR insulin had no discernable effect on pulmonary function. AIR insulin adverse events (cough, headache, and dizziness) were mild to moderate in intensity and have been previously reported or are typical of studies involving glucose clamp procedures. CONCLUSIONS: This study suggests that pulmonary disease severity and asthma treatment status influence the metabolic effect of AIR insulin in individuals with asthma but do not affect AIR insulin pulmonary safety or tolerability. In view of the potential interactions between diabetes treatment and pulmonary status, it is prudent to await the results of ongoing clinical trials in diabetic patients with comorbid lung disease before considering the use of inhaled insulin in such patients.

Conditional mixed models with crossed random effects.

The analysis of continuous hierarchical data such as repeated measures or data from meta-analyses can be carried out by means of the linear mixed-effects model. However, in some situations this model, in its standard form, does pose computational problems. For example, when dealing with crossed random-effects models, the estimation of the variance components becomes a non-trivial task if only one observation is available for each cross-classified level. Pseudolikelihood ideas have been used in the context of binary data with standard generalized linear multilevel models. However, even in this case the problem of the estimation of the variance remains non-trivial. In this paper, we first propose a method to fit a crossed random-effects model with two levels and continuous outcomes, borrowing ideas from conditional linear mixed-effects model theory. We also propose a crossed random-effects model for binary data combining ideas of conditional logistic regression with pseudolikelihood estimation. We apply this method to a case study with data coming from the field of psychometrics and study a series of items (responses) crossed with participants. A simulation study assesses the operational characteristics of the method.

AIR inhaled insulin in subjects with chronic obstructive pulmonary disease: pharmacokinetics, glucodynamics, safety, and tolerability.

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 = 15 each)--healthy subjects (baseline mean +/- SD age 38 +/- 13 years, forced expiratory volume in 1 s [FEV1] 4.06 +/- 1.04 l), subjects with chronic bronchitis (aged 53 +/- 9 years, FEV1 2.14 +/- 0.60 l), and subjects with pulmonary emphysema (aged 58 +/- 6 years, FEV1 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 administration 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 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, FEV1 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.