Format

Send to

Choose Destination

See 1 citation found by title matching your search:

See comment in PubMed Commons below
J Aerosol Med Pulm Drug Deliv. 2016 Oct 14. [Epub ahead of print]

Predicting Exposure After Oral Inhalation of the Selective Glucocorticoid Receptor Modulator, AZD5423, Based on Dose, Deposition Pattern, and Mechanistic Modeling of Pulmonary Disposition.

Author information

  • 1AstraZeneca R&D , Gothenburg, Sweden .

Abstract

BACKGROUND:

Exposure following oral inhalation depends on the deposition pattern of the inhaled aerosol, the extent and rate of oral and pulmonary absorption, as well as systemic distribution and clearance. For lipophilic inhaled compounds with low water solubility and high permeability, the extent and rate of pulmonary absorption can be assumed dependent on deposition pattern as well as dissolution rate.

MATERIALS AND METHODS:

A mechanistic model of airway deposition, mucociliary clearance, dissolution, absorption, and dissipation was applied to simulate systemic exposure of the novel selective glucocorticoid receptor modulator, AZD5423, when dosed to healthy volunteers using two different nebulizers and two different dry powder inhalers in combination with two different primary particle size distributions. Results from simulations were compared with observed pharmacokinetic data.

RESULTS:

Variations in systemic exposure (plasma concentration profile, AUC, and Cmax) resulting from variations in dose, deposition pattern, and dissolution rate could not be predicted solely from variations in delivered dose or predicted lung dose (as assessed using an anatomical mouth-throat model), suggesting incomplete pulmonary bioavailability. However, simulated systemic exposure well predicted observed systemic exposures for all tested formulations and devices. Furthermore, simulations of airway tissue exposure suggested that it was not directly linked to systemic exposure.

CONCLUSIONS:

Results support the initial hypothesis that systemic exposure of poorly soluble inhaled drugs is a complex but predictable function of dose, deposition pattern, and rate of dissolution. Furthermore, simulations indicate that local exposure for these types of drugs is not well correlated with systemic exposure. Hence, equivalence with respect to local exposure, and thus with respect to pharmacodynamic effect, cannot be fully inferred from systemic pharmacokinetic equivalence alone.

KEYWORDS:

AZD5423; anatomical mouth-throat model; deposition pattern; dissolution; inhalation; mechanistic modeling; pharmacokinetics; selective glucocorticoid receptor modulator; simulation

PMID:
27740878
DOI:
10.1089/jamp.2016.1306
[PubMed - as supplied by publisher]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Atypon
    Loading ...
    Support Center