TI is an inhaled insulin with a more rapid absorption and a more rapid elimination than subcutaneously administered RHI, resulting in a quick onset and short duration of action. Insulin exposure following TI administration was found to be linear over the dose range of 25-100 U.

Abbreviations: (ADME) absorption, distribution, metabolism, and excretion, ) area under the curve from time 0 to 480 minutes, (AUC 0-∞ ) area under the curve from time 0 to infinity, (AUC 0-t ) area under the curve from time 0 to t, (BMI) body mass index, (C last ) last observed insulin concentration, (CLD) chronic liver disease, (C max ) maximum observed drug concentration, (DNP) diabetic nephropathy, (FDKP) Bis-3,6(4-fumarylaminobutyl)-2, 5-diketopiperazine, (GFR) glomerular filtration rate, (HPLC) high-performance liquid chromatography, (LSC) liquid scintillation counting, (t 1/2 ) terminal elimination half-life, (t last ) time corresponding to last observed drug concentration, (t max ) time to maximum observed drug concentration Keywords: chronic liver disease, diabetic nephropathy, fumaryl diketopiperazine, inhalation, Technosphere

Multiple-compartment disposition of insulin has been demonstrated following intravenous administration; however, because of slow absorption and flip-flop kinetics, meal-time insulin pharmacokinetics have been described by a 1-compartment model. Technosphere insulin (TI) is an inhaled human insulin with rapid absorption and a distinct second compartment in its pharmacokinetics. The aim of this analysis was to develop a pharmacokinetic model for insulin administered via the intravenous, subcutaneous, and inhalation routes. A 2-compartment pharmacokinetic model with 1 (inhaled) or 2 sequential (subcutaneous) first-order absorption processes and first-order elimination was developed using data from 2 studies with a total of 651 concentrations from 16 healthy volunteers. Insulin was administered intravenously (5 U), subcutaneously (10 U), and via inhalation (25, 50, and 100 U). The data were modeled simultaneously with NONMEM VI, using ADVAN6 subroutine with FO. Typical values were clearance, 43.4 L/h; volume of distribution in the central compartment, 5.0 L; intercompartmental clearance, 23.9 L/h; volume of distribution in the peripheral compartment 30.7 L; TI first-order absorption rate constant, 2.35 h⁻¹; and first-order absorption rate constants associated with subcutaneously administered insulin, 0.63 and 1.04 h⁻¹, respectively. Absorption rate after subcutaneous dosing was found to decrease with increasing body mass index. Insulin pharmacokinetics were found to be consistent with 2-compartment disposition, regardless of route of administration, with insulin curve differences attributable to absorption differences.

The rapid insulin absorption and the resulting insulin pharmacokinetic profile following TI inhalation were not significantly altered in the mild-to-moderate COPD population studied; however, long-term safety and efficacy of TI have not been established in patients with mild or moderate COPD. Longer-term experience is needed to fully characterize the effects of COPD on insulin PK following TI administration.