Pharmacokinetic Characterization of the Novel Pulmonary Delivery Excipient Fumaryl Diketopiperazine

Abstract

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

Insulin Lung Deposition and Clearance Following Technosphere® Insulin Inhalation Powder Administration

“…Because of the limited blood sampling taken within this study, extensive serum pharmacokinetic analysis could not be performed. However, the data as reported are consistent with what has been reported in other pharmacokinetic and pharmacokinetic/pharmacodynamic studies where extensive blood sampling was conducted (2,11,14). The serum half-life of FDKP from this study (approximately 140 min) is equivalent to the 150 min half-life reported after IV administration (11), indicating that serum clearance is not absorption dependent.…”

“…Approximately 60% of the emitted dose is delivered to the lungs with a homogeneous distribution bilaterally throughout the lungs. The remaining~40% of the emitted material is not bioavailable as it is ultimately swallowed and enters the gastrointestinal tract, where neither the insulin nor the carrier molecule (FDKP) is absorbed (11). Although the plasma was analyzed for insulin, the low dose administered (due to radioactivity exposure limit) and the meal prior to dosing made it impossible to accurately determine the contribution of the exogenously administered insulin to the total insulin concentration.…”

“…As expected, the peak concentrations in the lungs were the first time point. The initial high concentration found in the lungs rapidly decreases as both insulin and FDKP are absorbed into the systemic circulation, from which the latter is excreted unchanged in the urine (11). The clearance from the lung ELF, as measured by serial BAL, is quite rapid with an apparent terminal half-life of~1 h for insulin and the carrier FDKP.…”

Inhaled Technosphere Insulin Compared With Injected Prandial Insulin in Type 1 Diabetes: A Randomized 24-Week Trial

“…Upon inhalation, these microparticles can reach the deep lung where they dissolve rapidly because of the physiological pH, allowing absorption of insulin and FDKP into the systemic circulation with a time to maximum serum insulin concentration of ;12-15 min (8,9). FDKP is excreted unchanged in the urine (10). TI is delivered through the Gen2 inhaler device.…”

New Insulins and New Aspects in Insulin Delivery

“…The excipient is also absorbed and excreted unchanged in the urine (73). The efficacy of prandially inhaled insulin has been tested in clinical trials as a prandial insulin added to basal insulin (74). Studies have shown that there may be less weight gain than occurs with other insulin regimens.…”