Introduction and Methodology

Absorption, distribution and clearance of triamcinolone acetonide (TA) from oral and pulmonary administrations have been simulated using GastroPlus™,1. Simulation of orally administered doses and swallowed portions of inhaled doses were simulated using the Advanced Compartmental Absorption and Transit (ACAT™) model within GastroPlus. The pulmonary delivery and pharmacokinetics model within GastroPlus (shown in Figure 1) has been used in earlier studies3-8. The model accounts for:

• mucociliary transit
• dissolution/ precipitation
• absorption into pulmonary cells
• nonspecific binding in mucus/ surfactant layers and cells
• (linear) metabolism
• transfer into the systemic circulation
• partial swallowing of the inhaled dose

Biopharmaceutical properties for TA (MW = 434.5) were generated using ADMET Predictor™ v5.02 or obtained from the literature9-15. Human lung physiological parameters (surface area, thickness, and volume for the mucus and cell) for each compartment were obtained from the literature16-18. Observed plasma concentration-time (Cp-time) profiles from a 2 mg intravenous (IV) bolus dose in humans (mean age = 29 years, mean weight = 81 kg) were used to fit a two-compartment PK model (using the PKPlus™ module of GastroPlus). The lumped systemic clearance was subsequently replaced by a Michaelis-Menten CYP3A4 clearance model for TA both in the liver and the GI tract. The Km was artificially set to a high value to represent nonsaturable conditions and the Vmax was fitted to the IV data. This PK model was used to describe systemic PK for all subsequent simulations. All oral and pulmonary simulations used the default human fasted state ACAT. Gut metabolism was described using the liver Km and Vmax values, with Vmax scaled in proportion to the ratio of the amount of CYP3A4 in gut and liver. Intestinal permeability was adjusted to match the oral Cptime slope prior to Cmax. For pulmonary simulations, human lung physiological compartment parameters were obtained from the literature. Although particle size distribution was not reported, it was obtained from an independent source for the same device19, and was used to calculate the fraction of the dose deposited in each lung compartment and fraction exhaled according to the built-in ICRP 66 model. A single value for the systemic absorption rate coefficient and linear metabolic clearance (representing possible metabolism, degradation, phagocytosis etc.) in all lung compartments was the only parameter fitted to match the pulmonary data.

Respiratory Drug Delivery (RDD), May 3-6, 2011, Berlin, Germany

By S. Ray Chaudhuri, Viera Lukacova, Walter S. Woltosz