Johanna Melin (1,2,3), Susanne Prothon (3), Charlotte Kloft (1), Adriaan Cleton (4), Carl-Christer Johansson (3), Carin Jorup (5), Bo Olsson (3), Ulrika Wählby Hamrén (3)
(1) Dept Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany
Objectives: AZD5423 is a non-steroidal glucocorticoid receptor modulator, with low aqueous solubility (<1 µM), developed for once daily treatment of asthma and COPD. In this work we aimed 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)) in two studies using differently sized primary particles, and to compare the pulmonary bioavailability (Fpulmonary) with the predicted lung deposited dose (according to Olsson [1]).
Methods: Plasma concentration-time data after intravenous, oral and inhaled administration via 4 devices were available from two clinical studies in healthy and asthmatic subjects. A population PK model was developed in a sequential manner, similar to [2-4], with parallel absorption compartments for inhaled AZD5423; a non-compartmental analysis was performed for comparison.
Results: Fpulmonary 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%). Fpulmonary were substantially lower than the predicted lung deposited dose (range 57-89%). Lung absorption was separated into a faster and a slower process. The half-life of the faster absorption appeared formulation-dependent, while the slower absorption (half-life of 35-47 min) appeared independent of formulation.
Conclusions: The large difference between the estimated Fpulmonary and the predicted lung deposited dose for AZD5423 in this study is likely caused by a high degree of mucociliary clearance. The low solubility did not result in significant lung retention.
References:
[1] Olsson B, Borgström L, Lundbäck H, Svensson M. Validation of a General In Vitro Approach for Prediction of Total Lung Deposition in Healthy Adults for Pharmaceutical Inhalation Products. J Aerosol Med Pulm Drug Deliv (2013) 26(6):355–69.
[2] Bartels C, Looby M, Sechaud R, Kaiser G. Determination of the pharmacokinetics of glycopyrronium in the lung using a population pharmacokinetic modelling approach. Br J Clin Pharmacol (2013) 76(6):868–79.
[3] Borghardt JM, Weber B, Staab A, Kunz C, Formella S, Kloft C. Investigating pulmonary and systemic pharmacokinetics of inhaled olodaterol in healthy volunteers using a population pharmacokinetic approach. Br J Clin Pharmacol (2015) ; doi: 10.1111/bcp.12780
[4] Melin J, Olsson BL, Johansson C, Kloft C, Wählby Hamrén U, Population pharmacokinetic analysis of AZD4818 in healthy volunteers following three different routes of administration, PAGE 2015
Reference: PAGE 25 () Abstr 5908 [www.page-meeting.org/?abstract=5908]
Poster: Drug/Disease modeling - Absorption & PBPK