Evolution of a Pulmonary Insulin Delivery System ( Exubera) for Patients With Diabetes

Priscilla A. Hollander, MD

Disclosures

March 05, 2007

The Pharmacokinetics and Pharmacodynamics of INH

The pharmacokinetics and pharmacodynamics of INH have been evaluated in an open-label, randomized, 3-way crossover euglycemic clamp study in 17 healthy male volunteers who received each of the following treatments in random order: inhaled INH 6 mg; insulin lispro 18 units SC; or regular human insulin 19 units SC.[13] Glucose infusion rates (GIR) and serum insulin concentrations were monitored over the following 10-hour period to allow comparison of the time-action profiles of each insulin formulation.

INH demonstrated a significantly more rapid mean time to maximal concentration (Tmax) than that of regular SC insulin (55 minutes vs 148 minutes, respectively, P < .001).[13] However, the mean maximal serum insulin levels (Cmax) were similar for both INH and regular SC insulin (66.9 mircroU/mL vs 61.0 microU/mL, respectively). Compared with regular SC insulin, the relative bioavailability of INH was 18% during the first hour after administration and 9% over the entire 10-hour study period, reflecting a rapid increase in serum insulin levels during this period.[13]

Gelfand and colleagues[14] conducted a 4-way, randomized-sequence, crossover study involving 2 inhalations of INH and 2 SC injections of regular insulin in 16 insulin-naive patients with type 2 diabetes. Analysis of postprandial glucose measurements and area under the concentration time curve (AUC) at various time points indicated that intrasubject variability was insignificant in all 16 patients, and that the pharmacokinetics of INH were equivalent to those of regular SC insulin in terms of reproducibility.[14]

A second study was conducted to ensure pharmacokinetic reproducibility in obese patients with type 2 diabetes.[15] In this randomized sequence, crossover design study, 10 men received 2 inhalations of insulin and 2 SC injections of regular insulin. As in the previous pharmacokinetic study, the pharmacokinetics and pharmacodynamics of INH showed very little intrasubject variability.[15]

The pharmacokinetics of INH have not been fully evaluated in individuals with pulmonary disease, such as mild-to-moderate asthma or chronic obstructive pulmonary disease (COPD), precluding its use in this patient population until these studies have been completed.

Consistent with the pharmacokinetic study results, INH demonstrated a significantly faster onset of action than both regular SC insulin and SC insulin lispro, as indicated by the shorter mean time to half-maximal effect: 32 minutes vs 48 minutes (P < .001) and 41 minutes (P < .05), respectively.[13] The mean time to maximal effect of INH was comparable to that of insulin lispro (143 minutes vs 137 minutes), but shorter than that of regular insulin (193 minutes; P < .01). Finally, the mean duration of the metabolic activity (time to late half-maximal effect) of INH was 387 minutes, significantly longer than that of insulin lispro (313 minutes, P < 0.01), and comparable to that of regular insulin (415 minutes).[13] The mean duration of metabolic activity was calculated as the time to late half-maximal effect and was assessed as the time to half of GIRmax after GIRmax (t GIR late 50%).

In summary, INH has a more rapid onset of action than subcutaneously administered regular human insulin or insulin lispro, with a duration of action exceeding that of insulin lispro and comparable to regular insulin. In addition, INH has shown very little intrasubject pharmacokinetic variability, even in obese patients. Taken together, these characteristics suggest that INH is well suited for prandial insulin supplementation in patients with diabetes.

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