Inhaled Insulin for Diabetes Mellitus

Tarun K. Mandal

Disclosures

Am J Health Syst Pharm. 2005;62(13):1359-1364. 

In This Article

Pharmacokinetic Considerations

In humans, inhaled regular insulin is more rapidly absorbed (peak concentrations achieved in 49–65 minutes) than insulin from the subcutaneous injection site (peak concentrations achieved in 119 minutes).[21] The time to reach maximum insulin concentration in blood following inhalation (tmax) is comparable to that of subcutaneous injection with the two fast-acting DNArecombinant insulin analogs, insulin lispro (Humalog [Eli Lilly]) and insulin aspart (Novolog [Novo Nordisk]). The duration of action of inhaled insulin is slightly longer than that following subcutaneous administration of insulin lispro or insulin aspart (four to six hours versus three to five hours, respectively) but is slightly shorter than the duration of action of subcutaneous administration of regular insulin (four to six hours versus four to eight hours, respectively).[22] The quick absorption profiles following inhalation suggest that rapid glycemic control at mealtimes may be achieved with inhaled insulin, similar to that of fast-acting recombinant insulin analogs. These observations suggest that with pulmonary insulin delivery systems, patients may be able to inhale a dose 5–10 minutes before a meal to achieve adequate glycemic control rather than the 20–30 minutes necessary with subcutaneous insulin injections. However, inhaled regular insulin should be used in combination with a once-daily injection of long-acting insulin because of the shorter duration of action following absorption through the pulmonary route.

The efficiency of inhaled insulin is lower than that of subcutaneous injection because pulmonary delivery of insulin involves some loss of drug within the inhaler or mouth during inhalation. Before insulin reaches the absorptive surface of the lungs, there are losses of drug in the throat and nonabsorptive surfaces of the upper respiratory tract. During inhalation, only 20–30% of the administered dose reaches the peripheral lung region for systemic absorption. Approximately 25–50% of an inhaled insulin dose remains in the device or goes directly or indirectly (after being brought out of the lungs by the bronchial cilia transport mechanism) into the oropharynx and is swallowed. Regardless of the system used for pulmonary delivery, the bioavailability of inhaled insulin is relatively low (less than 20%), so a very high dose, as much as eight to nine times the subcutaneous dose, is required to achieve the same glucoselowering effect.[23] The dosage requirements for orally inhaled insulin may lead to a significantly higher cost per treatment, but the manufacturers have not yet addressed this issue.

Variability of insulin absorption is not only associated with the pulmonary route. A number of studies have been published describing the variability of insulin absorption following subcutaneous administration. A thorough review of the variability of insulin absorption and action has been published by Heinemann.[3] In summary, after subcutaneous administration of regular insulin, the intraindividual coefficient of variation (CV) was 15–25%, and the CV was over 10% for interindividual comparison studies. The interindividual CV was over 50% for subcutaneous administration of intermediateand long-acting insulin. Variability of absorption in a study of healthy volunteers who received an identical insulin dose by oral inhalation for three study days led to an intraindividual CV that was comparable to that observed after subcutaneous administration of regular insulin. In another dose–response study with patients with type 1 diabetes, the intraindividual CV was 34%. The variability of inhaled insulin absorption was equal to or less than that seen after subcutaneous administration of insulin in patients with type 2 diabetes. However, the variability of insulin absorption is not always a predictor of insulin action, since an identical insulin dose does not always provide identical metabolic response in patients with diabetes. Irrespective of the route of administration, the variability of insulin absorption in diabetic patients is also affected by differences in insulin sensitivity.

Absorption of inhaled insulin may also be affected by age or the presence of an upper-respiratory-tract infection or respiratory disease. In a study of young (18–45 years of age) and elderly (≥65 years of age) patients with type 2 diabetes, absorption was comparable following a single inhalation of insulin using AERx iDMS but less glucose reduction was reported in the elderly patients.[24] In a similar study using the AERx iDMS, no significant change in the extent of absorption was reported based on age.[24] Absorption of orally inhaled insulin has not been studied in patients with common lung diseases such as asthma and cystic fibrosis. Patients suffering from asthma or cystic fibrosis could show significant changes in alveolar deposition of inhaled insulin.

Absorption of inhaled insulin is also affected by smoking. In a study of nondiabetic active smokers without apparent pulmonary disease, the absorption rate of inhaled insulin increased by as much as 50% (area under the exogenous serum insulin curve from zero to six hours [AUC0–6], 63.2 milliunits/L/hr versus 40.0 milliunits/L/hr) and the time to reach peak concentration was decreased up to 40% (31.5 minutes versus 53.9 minutes).[25] Becker et al.[26] studied the effect of smoking cessation and subsequent resumption on absorption of orally inhaled insulin. This study compared the absorption of inhaled insulin in nondiabetic active smokers (smoking an average of 16 cigarettes/day) at baseline, after smoking cessation, and after smoking resumption with that of nonsmokers. Smoking cessation decreased the AUC0–6 up to 50% within one week, close to the AUC0–6 observed in nonsmokers, although the maximum serum concentration and tmax still indicated faster absorption in the smokers following smoking cessation. Smoking resumption completely reversed the effects of smoking cessation on the AUC. These observations suggest that patients with diabetes should abstain from smoking before and during treatment with inhaled insulin to avoid unanticipated results of the treatment. Additional study is needed to determine the effects of smoking on the pharmacokinetics and efficacy of orally inhaled insulin in patients with diabetes.

processing....