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

Abstract

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.

Safety, Pharmacokinetics and Pharmacodynamics of the Selective Glucocorticoid Receptor Modulator AZD5423 after Inhalation in Healthy Volunteers

“…In the current study, two different nebulizers were used – one more appropriate for an experimental setting early in a drug development programme (Spira), and one commercially available nebulizer more convenient for patient use and big trial settings (I‐neb). Delivered doses from Spira ranged from 8 to 1248 μg in the SAD (study A) and 125 to 499 μg in the MAD (study B), where most is deposited peripherally in the lung . The predicted fraction which is peripherally deposited (i.e.…”

In Silico Methods for Development of Generic Drug–Device Combination Orally Inhaled Drug Products

“…Only a few studies have used the Pulmonary Compartmental Absorption & Transit (PCAT) model in Gastroplus to model absorption from OIDPs . The effect of different carrier properties on systemic PK was investigated by Wu et al .…”

“…Salar‐Behzadi et al . and Bäckman et al . used intravenous data to estimate clearance, whereas others did not, presumably because they were unavailable .…”

“…Only a few studies have used the Pulmonary Compartmental Absorption & Transit (PCAT) model in Gastroplus to model absorption from OIDPs. 70,[81][82][83] The effect of different carrier properties on systemic PK was investigated by Wu et al 81 who measured APSD from two formulations of albuterol sulfate using the Cyclocaps capsules Teva UK, Harlow, UK in an Aerolizer device, where glass beads were used as carrier particles as opposed to lactose because of the ease of surface modification. Values of maximum plasma concentration (C max ) and FPF were increased by factors of 1.20 and 1.36, respectively, for the formulation where the glass bead surface was modified as opposed to the formulation with the unmodified glass beads.…”

“…81 The predictive power of deposition and permeability estimates provided by the Gastroplus PCAT model when compared with in vivo deposition data and experimentally determined alveolar permeability data was tested by Salar-Behzadi et al, 82 where predictions of C max and area under the time-concentration curve from time 0 to time t from Turbuhaler (budesonide DPI) when compared with available PK data were greatly improved by the addition of experimental data. Bäckman et al 83 used Gastroplus PCAT to model the exposure of a poorly soluble investigational compound, AZD5423, using a number of delivery methods, including different nebulizers and DPI devices, where it was found that total lung deposition values from an in vitro model were not alone predictive of differences in PK metrics, but when deposition pattern and dissolution were also considered, the predictions matched well with available PK data.…”