Aerosolized protein delivery in asthma: Gamma camera analysis of regional deposition and perfusion

Bioavailability of an aerosolized anti-inflammatory protein, soluble interl eukin-4 receptor (IL,4R), was measured in patients with asthma using two di fferent aerosol delivery systems, a prototype aerosol delivery system (AERx ((R)) tethered model, Aradigm, Hayward, CA) and PARI LC STAR((R)) nebulizer (Pari, Richmond, VA). Regional distribution of the drug in the respiratory tract obtained by planar imaging using gamma camera scintigraphy was utili zed to explain the differences in bioavailability. The drug, an experimenta l protein being developed for asthma, was mixed with radiolabel (99m)Techne tium diethylene triaminepentaacetic acid (Tc-99m-DTPA). Aerosols were chara cterized in vitro using cascade impaction (mass median aerodynamic diameter [MMAD] and geometric standard deviation [GSD]); the AERx((R)) MMAD 2.0 mum (GSD 1.35), the PARI((R)) 3.5 mum (GSD 2.5). Four patients with asthma req uiring maintenance aerosolized steroids were studied. First, regional volum e was determined utilizing equilibrium Xe-133 scanning. Then, after a brief period of instruction, patients inhaled four breaths of protein using AERx ((R)) (0.45 mg in total) followed 1 week later by inhalation via PARl((R)) (3.0 mg nebulized until dry). Each deposition image was followed by a measu rement of regional perfusion using injected Tc-99m albumin macroaggregates. Deposition of Tc-99m-DTPA in the subjects was determined by mass balance. Regional analysis was performed using computerized regions of interest. The regional distribution of deposited drug was normalized for regional volume and perfusion. Following each single inhalation, serial blood samples were drawn over a 7-day period to determine area under the curve (AUC) of prote in concentration in the blood. Median AUC(AERx)/AUC(PARI) was 7.66/1, based on the amount of drug placed in each device, indicating that AERx((R)) was 7.66 times more efficient than PARI((R)). When normalized for total lung d eposition (AUC per mg deposited) the ratio decreased to 2.44, indicating th at efficiencies of the drug delivery system and deposition were major facto rs. When normalized for sC/P and (pU/L)(Xe), ratios (central to peripheral and upper to lower ratios are parameters of regional distribution of deposi ted particles and regional perfusion ['p ']), AUC(AERx)/AUC(PARI) further d ecreased to 1.35, demonstrating that peripheral sites of deposition with th e AERx((R)) affected the final blood concentration of the drug. We conclude that inhaled bioavailability of aerosolized protein, as expressed by AUC, is a quantifiable function of lung dose and regional deposition as defined by planar scintigraphy.