Abstract

Objective: To simulate and predict the absorption and pharmacokinetics (PK) of budesonide following orally‐inhaled (OIN) i.e. respiratory administration across multiple formulations and/or devices.

Methodology: All OIN formulations distribute both in the lungs and extra‐pulmonary compartments such as oral cavity, larynx, pharynx, etc., the latter leading to swallowing and absorption through the gastrointestinal (GI) tract. The relative proportion of distribution in these two regions is a function of the formulation characteristics, device properties, administration conditions, and environmental factors. Thus, a robust mathematical model representing OIN formulations should contain appropriate respiratory, GI, and systemic components. In the current work, we apply a mathematical model to describe OIN administration of budesonide (a glucocorticosteroid with high local anti‐inflammatory effects) across a variety of formulations and devices. The OIN component was modeled using a mechanistic physiologically based Pulmonary Compartmental Absorption & Transit (PCAT™) model that has been successfully used before. Recently, we developed a model describing disposition of budesonide in human subjects after intravenous (IV) and peroral (PO) doses using GastroPlus™ [1], which incorporates the proprietary Advanced Compartmental Absorption and Transit (ACAT™) model to simulate GI absorption (from oral doses). A PBPK model was used to describe the systemic PK. This model was used without further adjustment to describe the extra‐pulmonary components of the OIN model. The only fitted pulmonary parameter across all formulation and device conditions was the first‐order kinetic rate constant for systemic uptake from lung, fitted against plasma concentration‐time (Cp‐time) profiles following 0.8 mg of budesonide powder from a Turbuhaler™ device [2]. This model was then used without any further modification to predict the disposition of (a) 0.37 mg administrations of PulmoSphere™ powder from an Eclipse™ DPI both at low (29 L/min) and high (44 L/min) flow rates [2], and (b) 1 mg powdered budesonide from a Clickhaler™ [3]. In all cases, reported oropharynx and lung deposition values were used to obtain PCAT deposition fractions. The model was then used to predict the disposition of nanocrystalline budesonide from a PARI LC JetPlus™ Nebulizer [4]. In this case, reported particle sizes of 75–300 nm were used in conjunction with a flow rate of 8 L/min [4] to predict in vivo deposition in the lung and extra‐pulmonary compartments using the ICRP66 deposition model [5].

American Association of Pharmaceutical Scientists (AAPS), November 10-14, 2013, San Antonio, TX

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