J. Borghardt (1, 2), A. Staab (2), C. Kunz (2), J. Schiewe (2), C. Kloft (1)
(1) Dept. Clinical Pharmacy & Biochemistry, Freie Universitaet Berlin, Germany; (2) Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Objectives: As there is a lack of quantitative mechanistic understanding about plasma concentration-time profiles after inhalation of drug formulations, the objective of this work was to initiate a workflow to increase the understanding about how deposition, dissolution and absorption of drugs after inhalation impact their plasma concentration-time profiles [1, 2]. Therefore the different absorption rates of a long acting beta-agonist, olodaterol, administered as a solution, were investigated.
Methods: Plasma concentration-time profiles after intravenous infusion, oral and inhalative administration were available from different trials in healthy volunteers. The analyses were performed using NONMEM VII and R. First, a model for the intravenous data has been developed which allowed to simulate a typical concentration-time profile after a bolus injection of olodaterol. This profile was then used as a weight function for a numerical deconvolution (area-point method coded in R) to characterise the absorption behaviour in the lung after inhalation.
Results: By deconvolving the geometric mean concentration-time profile after inhalation with the weight function the unabsorbed fraction per time was calculated. By plotting these values versus time in a semilogarithmic graph the slope between two points could be computed. This slope resembled the negative absorption rate constant at a given time. Hence, it was shown that the absorption kinetics of olodaterol administered by inhalation was best described by several first-order absorption rate constants. The highest contributed to the early tmax after 10 to 20 minutes, whereas the lowest caused drug uptake even after several hours.
Conclusions: The results obtained are in agreement with physiological characteristics of the lung. Particles deposited in the alveolar space may be absorbed fast, whereas absorption of particles deposited in the conducting airways may be slow. As the bioavailability of olodaterol after oral administration was shown to be negligible a slower absorption process due to swallowed droplets can be ruled out. As a next step, the fractions absorbed associated with a certain absorption rate constant will be determined and then will be correlated with the total lung dose and the droplet distribution patterns across the lung described by an in vitro Finlay-throat assay [3]. Furthermore, these fractions will be included into a semi-mechanistic model to predict concentration-time profiles.
References:
[1] J.L. Sporty, L. Horálková, C. Ehrhardt. In vitro cell culture models for the assessment of pulmonary drug disposition. Expert Opin Drug Metab Toxicol 4(4): 333-345 (2008).
[2] R. Labiris, M.B. Dolovich. Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol 56(6): 588-599 (2003).
[3] A. Johnstone, M. Uddin, A. Pollard, A. Heenan, W.H. Finlay. The flow inside an idealised form of the human extra-thoracic airway. Exp Fluids 37: 673-689 (2004).
Reference: PAGE 22 (2013) Abstr 2895 [www.page-meeting.org/?abstract=2895]
Poster: Absorption and Physiology-Based PK