Pharmacokinetics of the Inhaled Selective Glucocorticoid Receptor Modulator AZD5423 Following Inhalation Using Different Devices

Johanna Melin, Susanne Prothon, Charlotte Kloft, Adriaan Cleton, Carl Amilon, Carin Jorup, Per Bäckman, Bo Olsson, Ulrika Wählby Hamrén

AZD5423 is a non-steroidal glucocorticoid receptor modulator, with low aqueous solubility, developed for treatment of asthma and COPD. In this work, we aim to evaluate and compare the absorption pharmacokinetics (PK) of AZD5423 after inhalation via four devices, (Spira®, I-neb®, Turbuhaler® and a new dry powder inhaler (new DPI)) with two formulations using differently sized primary particles, and to compare the pulmonary bioavailability with the predicted lung deposited dose. Plasma concentration-time data after intravenous, oral and inhaled administration via four devices were available from two clinical studies in healthy and asthmatic subjects. A population PK modelling approach was taken to sequentially incorporate each route of administration, assuming parallel absorption compartments for inhaled AZD5423. A non-compartmental analysis for derivation of PK parameters was performed for comparison. Pulmonary bioavailability varied between devices, with the lowest estimates for I-neb (27%) and Turbuhaler (30%) and the highest for the new DPI (46%) and Spira (35-49%). The pulmonary bioavailability was substantially lower than the predicted lung deposited dose (range 59-90%). Lung absorption was separated into a faster and a slower process in the model. The half-life of the faster absorption appeared formulation-dependent, while the slower absorption (half-life of 0.59-0.78 h) appeared independent of formulation. The large difference in the estimated pulmonary bioavailability and the predicted lung deposited dose for AZD5423 implies an impact of mucociliary clearance. The lung absorption half-life indicates that AZD5423 is retained in the lung for a relatively short time.