Scope and relevance of a pulmonary biopharmaceutical classification system AAPS/FDA/USP Workshop March 16-17th, 2015 in Baltimore, MD

Abstract

The Biopharmaceutics Classification System (BCS), developed in the 1990s for oral immediate release drugs, is utilized by R&D scientists and regulators to streamline product development and regulatory approval timelines. This elegant, science-based approach is based on three in vitro parameters representing a combination of drug substance physicochemical and physiological properties with respect to oral administration; specifically a dose number, dissolution number, and absorption number. Interest in applying similar principles to pulmonary drug products is increasing. To date the focus has been on dissolution of drugs in the lung. A workshop co-sponsored by the AAPS, FDA, and USP was held in March 2015 in Baltimore to evaluate if a systematic framework to classify pulmonary drugs could be established, and the scope and relevance of such a classification scheme. The focus of the workshop was to address factors influencing drug delivery and action in the lungs rather than the development of a specific model or system. Presentations included: the history and evolution of the oral BCS (described as the "giBCS" by Gordon Amidon), lung physiology and the fate of inhaled drugs, regional aerosol deposition and dose, macroscopic clearance mechanisms, particle dissolution, drug permeability, absorption and their interplay with pharmacokinetics and pharmacodynamics. Background discussions were followed by three separate breakout sessions each focused on the BCS concepts of dose, dissolution, and absorption numbers as they would apply to pulmonary drug delivery. The workshop concluded that a classification system, if fully developed, would be a useful tool for formulators and discovery chemists. The scope of such a system, at this point in time, would not include aspects relevant to regulatory relief. The goals of the workshop were met by identifying an opportunity to develop a model to classify pulmonary drugs based on physicochemical attributes specific to lung physiology and drug delivery.

A Comparison of Drug Transport in Pulmonary Absorption Models: Isolated Perfused rat Lungs, Respiratory Epithelial Cell Lines and Primary Cell Culture

“…The physicochemical properties of molecules that confer good biopharmaceutical performance when inhaled are not fully understood [6,37,38]. In vitro and ex vivo techniques provide experimental models in which drug permeability in the lungs can be derived empirically.…”

“…A recent AAPS/FDA/USP workshop considered a systematic framework to classify pulmonary drugs to provide a tool for formulators and discovery chemists working in the pulmonary drug delivery field [6]. Drug permeability or the rate of absorption was identified as an important predictor of local residence time and, therefore, duration of effect for locally-acting drugs.…”

“…Drug permeability in respiratory epithelial cell lines is well-correlated with the pulmonary absorption rate constant in rats [12,16], which makes the cell lines useful for rank-ordering and screening drugs with respect to their intrinsic lung absorption rates [6]. We compared directly the permeability of seven molecules in Calu-3, 16HBE14o- and NHBE cell layers, deriving log-linear relationships between their permeability in Calu-3, 16HBE14o- or NHBE cell layers and the absorption rate constant determined after pulmonary delivery to rats (Fig.…”

“…Although in vitro epithelial cell culture [4] and ex vivo lung methods [5] are available to screen the permeability of drug candidates for development as orally inhaled products, there is no standard experimental method for measuring drug permeability or predicting lung absorption [2]. As drug permeability in the lungs has been proposed recently to be a key factor in a biopharmaceutical classification system being developed for inhaled compounds (iBCS; [6]), the validation of screening techniques for predicting absorptive clearance from the lungs is of high importance.…”

Engineered sodium hyaluronate respirable dry powders for pulmonary drug delivery

“…Hence, the stearyl alcohol that potentially reaches the lung can be estimated to be approximately 0.1 mg (5% of the 1.98 mg respirable dose). Although not taking into account local concentration gradients during particle dissolution, solubilisation of this dose in the available volume of lung lining fluid (20 mL based on estimates of 10-30 mL in the conducting airways and 7-20 mL in the alveolar region (Hastedt et al, 2016), would provide a surfactant concentration of around 5 µg/ml, namely 0.018 mM, which compares very favorably to an LC50 = 24.7 mg/mL in vitro. Therefore, this data represent a preliminary encouraging step toward the gain the FDA approval for this new excipients .…”