Dose Response of Inhaled Dry-Powder Insulin and Dose Equivalence to Subcutaneous Insulin Lispro

Abstract

OBJECTIVE -To determine the pharmacokinetic (PK) and glucodynamic (GD) dose response of human insulin inhalation powder (HIIP) delivered via AIR particle technology and dose equivalence to subcutaneous (SC) insulin lispro.RESEARCH DESIGN AND METHODS -Twenty healthy, nonsmoking, male or female subjects (aged 29.6 Ϯ 6.9 years, BMI 23.2 Ϯ 2.3 kg/m 2 , means Ϯ SD) with normal forced vital capacity and forced expiratory volume were enrolled in an open-label, randomized, sevenperiod, euglycemic glucose clamp, cross-over trial. Each subject received up to four single doses of HIIP (2.6, 3.6, 5.2, or 7.8 mg) and three doses of SC lispro (6, 12, or 18 units) from 5 to 18 days apart.RESULTS -HIIP demonstrated a similar rapid onset but an extended time exposure and a prolonged duration of effect (late t 50% 412 vs. 236 min, P Ͻ 0.001) compared with SC lispro. The HIIP versus SC lispro doses of 2.6 mg vs. 6 units, 5.2 mg vs. 12 units, and 7.8 mg vs. 18 units achieved similar PK area under the serum immunoreactive insulin (IRI) concentration-versustime curve from time zero until the serum IRI concentrations returned to the predose baseline value [AUC (0-tЈ) ] and GD (G tot ) responses. The median insulin (t max ) was not different between HIIP and SC lispro (45 min for both), although the median time of return to baseline for PK was apparently longer for HIIP compared with SC lispro (480 vs. 360 min). Relative bioavailability and relative biopotency of HIIP were consistent across doses (8 and 9%).CONCLUSIONS -While the time-action profile was longer for HIIP than for SC lispro, both treatments showed rapid initial absorption and similar overall PK exposure and GD effect. HIIP was as well tolerated as SC lispro, thereby offering a promising alternative to injectable insulin therapy. Diabetes Care 28:2400 -2405, 2005T he disease burden of diabetes continues to grow and currently affects Ͼ18 million Americans and their families (1). Despite increased use of diabetes medications (without, however, increased utilization of insulin), overall diabetes control A1C among individuals diagnosed with diabetes in the U.S. has not improved, with A1C rising from 7.7 to 7.9% during the final decade of the last century (2). These data emphasize a need for alternative diabetes therapies with earlier more physiologic use of insulin.The delivery of insulin by the lung may provide an attractive alternative for many patients with diabetes (3-8). However, alternative insulin delivery systems must meet certain pharmacokinetic (PK) and glucodynamic (GD) requirements to reach maximum utility (9). Specifically, the dose-response characteristics of inhaled insulin should be similar to those of injectable insulins, like human regular insulin or fast-acting insulin analogs such as insulin lispro. Moreover, inhaled insulin should demonstrate satisfactory dose reproducibility; that is, intrasubject variability of inhaled insulin should be similar to or better than that of injectable insulin. Finally, the ratio of dose equivalence between inhaled insulin an...

Efficacy and safety of preprandial human insulin inhalation powder versus injectable insulin in patients with type 1 diabetes

“…A previous study has shown that the human inhaled insulin powder (HIIP) used in the present study is well tolerated and has a good safety profile [10]. Moreover, HIIP demonstrated a broad range of dose proportionality relative to subcutaneously injected insulin lispro, as well as comparable glucodynamic effects and intra-subject variability.…”

“…The incidence of severe Data expressed in insulin units, least squares means (SE). No significant differences were observed between the treatments for any of the dosing parameters listed here HIIP doses represent SC unit equivalents that were determined previously in a euglycaemic clamp study conducted in normal volunteers [10] hypoglycaemia was similar for the HIIP and SC insulin treatment periods (12 (Fig. 5b).…”

“…The low-dose capsules were filled with 0.9 mg of insulin, equivalent to 2 U of SC insulin. Mediumdose capsules were filled with 2.6 mg of insulin, equivalent to 6 U of SC insulin [10]. Capsules were loaded into a breath-actuated inhaler (pre-commercial model), which contained a puncturing mechanism to allow release and dispersal of insulin from the capsule without requiring an external energy source.…”

Guidelines for Optimal Bolus Calculator Settings in Adults

“…6 A short DIA hides residual bolus insulin activity, causes unrecognized insulin stacking, and may lead to errors in other settings as the user attempts to compensate for this hidden insulin stacking. One study found that the DIA appeared to depend on the size of the insulin dose, 8 but this apparent dose/time dependency may be an artifact of the glucose infusion rate (GIR) methodology used. In this and Mudaliar's GIR study, the DIA or insulin pharmacodynamics was measured as the time over which glucose infusion was needed to offset an insulin bolus given to healthy individuals.…”

The clinical effectiveness and cost-effectiveness of inhaled insulin in diabetes mellitus: a systematic review and economic evaluation

“…4 Currently, inhaled insulin is restricted to a shortacting profile and for almost all patients would not completely remove the need for injection. A study by Rave and colleagues 34 compared the timeaction profile of one inhaled insulin, Exubera, with that of a subcutaneously injected insulin analogue, lispro, or regular human soluble insulin in healthy volunteers. Inhaled insulin was found to have a faster onset of action than regular insulin, but was comparable to lispro.…”