Johanna Melin (1)(2)(3), Bo L Olsson (3), Carl Johansson (3), Charlotte Kloft (1), Ulrika Wählby Hamrén (3)
(1) Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany, (2) Graduate Research Training Program PharMetrX, Germany, (3) AstraZeneca R&D, Mölndal, Sweden.
Background: The pharmacokinetics (PK) of drugs administered via inhalation may be different in comparison to when administered intravenously. Several factors such as solubility, mucociliary clearance, pulmonary disposition patterns, lung anatomy and disease status may affect the PK and thereby also the pharmacodynamics (PD) of inhaled drugs [1]. Population PK analyses have previously been performed to quantify the different lung absorption processes, thereby increasing the mechanistic understanding of inhaled drugs [2, 3]. To this end, an in-house compound (AZD4818) previously in development for COPD was selected as model drug. AZD4818 is a water soluble base with expected limited mucociliary clearance.
Objectives: This analysis aims to use a population PK approach to characterize the pharmacokinetics of AZD4818 after intravenous (iv), oral (po) and pulmonary (pi) administration and to evaluate the impact of the lung PK on the apparent systemic PK.
Methods: Data from a single-dose 4-way cross over study in healthy volunteers (N=12) following iv, po and pi (with two devices: one dry powder inhaler, and one nebuliser) administration of AZD4818 were used for model development. Plasma and urine concentration-time data were included in the analysis using NONMEM 7.3 and PsN 4.2.0 [4,5]. The PK disposition model was developed on data after iv administration and data following pi and po administration were sequentially included to estimate absorption specific parameters. Similar approaches have previously been used [2,3]. GOF plots, model convergence, precision of parameter estimates and visual predictive checks were used to evaluate model performance.
Results: A three compartment disposition model with renal and non-renal clearance described the data after all administration routes adequately. Absorption processes were described separately for pi and po administration, and the pulmonary administration included three rate constants. A major proportion of the inhaled dose was absorbed with the slowest absorption rate, potentially explaining the absorption-rate limited elimination (flip-flop kinetics) observed after inhalation. Small differences in absorption pattern between the two devices were observed.
Conclusions: The proposed model, separating and quantifying the different absorption processes for inhaled AZ4818, may be applied on future inhalation compounds to evaluate the effect of drug- and inhalation device-specific factors on absorption-related parameters.
References:
[1] Olsson B, Bondesson E, Borgström L, Edsbäcker S, Ekelund K, Gustavsson L, et al. Controlled Pulmonary Drug Delivery. Smyth HDC, Hickey AJ.Springer New York, New York, 21-50, 2011.
[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, Schiewe J, Kloft C. Expanding the Mechanistic Knowledge About Pulmonary Absorption Processes Using a Population Pharmacokinetic Model for Inhaled Olodaterol. Respir Drug Deliv (2014):417–22.
[4] Beal S, Sheiner LB, Boeckmann A, Bauer RJ, NONMEM User’s guides. 1989-2009. Icon Development Solutions, Ellicott City, Maryland, USA.
[5] Lindbom L, Pihlgren P, Jonsson EN, Jonsson N. PsN-Toolkit–a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed (2005) 79(3): 241–57.
Reference: PAGE 24 (2015) Abstr 3570 [www.page-meeting.org/?abstract=3570]
Poster: Drug/Disease modeling - Other topics