Pharmacokinetics of the Inhaled Selective Glucocorticoid Receptor Modulator AZD5423 Following Inhalation Using Different Devices
- 348 Downloads
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.
KEY WORDSglucocorticoid receptor inhalation pharmacokinetics
The authors wish to thank Staffan Edsbäcker for input during the review process.
Compliance with Ethical Standards
Both studies were conducted in accordance with the provisions of the Declaration of Helsinki (1996) and the Good Clinical Practice guidelines (1996). Study protocols were approved by the ethics committees Guy’s Research Ethics Committee London, UK (study A) and NRES Committee, London, UK (study B). All subjects gave their written informed consent before participating in the trials.
- 1.Gauvreau AGM, Boulet L, Leigh R, Donald W, Killian KJ, Davis BE, et al. A non-steroidal glucocorticoid receptor agonist inhibits allergen-induced late asthmatic responses. Am J Respir Crit Care Med. 2015;191:161–7. doi: 10.1164/rccm.201404-0623OC.
- 2.Hansson T, Berger M, Dahmen J, Edman K, Eriksson A, Gabos B, et al. Discovery of AZD5423, a potent and selective non-steroidal glucocorticoid receptor modulator for the inhaled treatment of respiratory diseases. Presentation presented at 245th National Meeting of the American Chemical Society, New Orleans, LA; 2013. Abstract MEDI-278.Google Scholar
- 3.Werkström V, Prothon S, Ekholm E, Jorup C, Edsbäcker S. Safety, pharmacokinetics and pharmacodynamics of the selective glucocorticoid receptor modulator AZD5423, following inhalation in healthy volunteers. Basic Clin Pharmacol Toxicol. 2016;119:574–81. doi: 10.1111/bcpt.12621.CrossRefPubMedGoogle Scholar
- 4.Olsson B, Bondesson E, Borgström L, Edsbäcker S, Ekelund K, Gustavsson L, et al. Pulmonary drug metabolism, clearance, and absorption. In: Smyth HDC, Hickey AJ, editors. Controlled pulmonary drug delivery. New York: Springer New York; 2011. p. 21–50.Google Scholar
- 8.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. 2016;81:538–52. doi: 10.1111/bcp.12780.CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Parra-Guillen ZP, Weber B, Sharma A, Freijer J, Retlich S, Borghardt JM, et al. Population pharmacokinetic analysis of tiotropium in healthy volunteers after intravenous administration and inhalation. J Pharmacokinet Pharmacodyn. 2014;41 Suppl 1:S54. doi: 10.1007/s10928-014-9379-8.
- 12.Global Strategy for Asthma Management and Prevention, Global initiative for asthma (GINA). GINA Report. 2009. http://www.ginasthma.com
- 13.Bäckman P, Tehler U, Olsson BL. Predicting exposure after oral inhalation of the Selective Glucocorticoid Receptor Modulator AZD5423 based on dose, deposition pattern and mechanistic modeling of pulmonary disposition. J Aerosol Med Pulm Drug Deliv. 2016. doi: 10.1089/jamp.2016.1306.PubMedGoogle Scholar
- 15.R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria; 2016. http://www.r-project.org/
- 20.ICRP. Human respiratory tract model for radiological protection. ICRP publication 66. Ann ICRP. 1994; 24.Google Scholar