While being indispensable in the therapeutic management of many lung diseases, orally inhaled drug products (OIDPs) constitute a significant healthcare cost burden in the United States and worldwide. Thus, their generic development and entry are being sought, yet regulatory methods/paths to assess generic bioequivalence with the reference (innovator) product have not yet been established. The FDA Office of Generic Drug (OGD) initiated a study to evaluate the sensitivity of pharmacokinetics to differences in the aerodynamic particle size distribution (APSD) for three different, investigational dry powder inhaler (DPI) formulations of a poorly soluble inhaled corticosteroid (ICS), fluticasone propionate (FP) [RFA-FD-13-014]. This is to identify key drug and formulation variables and device performances to establish proper equivalency limits and design a possible path forward for generic bioequivalence. Accordingly, this cooperative research agreement project with FDA is to assist this OGD's study by developing an in vitro dissolution test method for OIDPs, capable of predicting APSD-dependent lung deposition and absorption following inhalation in humans, when aerosol drug dissolution is rate-determining in the lung. We hypothesize that such in vitro aerosol drug dissolution rates can be used in a newly developed semi-physiological lung deposition and disposition kinetics model to explain or extrapolate APSD-dependent pharmacokinetics of the FP aerosols for OGD's three investigational DPIs.
In Aim 1, we will validate our modified in vitro fluid capacity-limited Transwell(R)-based aerosol dissolution system using reference OIDPs, Flovent HFA(R) and Diskus(R) to identify the experimental setup variables to best predict in vivo pulmonary dissolution rates, and to assess the sensitivity of differentiating APSD-dependent dissolution rates.
In Aim 2, using the dissolution system, established in Aim 1, we will determine the dissolution rates (i.e., kdiss values) for the "respirable" (d 5.8 or 6.5 mm) drug aerosols generated from OGD's three investigational FP-DPIs and commercial ICS-OIDPs. The kdiss values will be correlated with the "respirable" doses and/or APSDs provided or measured in this project for their use in Aim 3, in addition to the solubility.
In Aim 3, using the semi- physiological lung deposition and disposition kinetics model, we will attempt to predict the FP pharmacokinetics following inhalation of OGD's three FP-DPIs from the in vitro kdiss values experimentally determined in Aim 2, and to fit the observed FP plasma concentration-time profiles provided by OGD, together with the compendial APSD data, in order to derive the best estimates for the in vivo clinical kdiss values to be correlated with the in vitro kdiss values. The proposed study will be completed in one year with three personnel and our Bioanalytical Share Resource Laboratory. If successful, as proposed, this novel systems and approach could prospectively supplement or supplant the formal in vivo bioequivalence assessment, i.e., pharmacokinetic equivalence studies in humans, as a part of their bioequivalence demonstration for poorly soluble ICSs such as FP, and possibly mometasone furoate and fluticasone furoate.
RELEVANCE While being indispensable in many lung disease managements, orally inhaled drug products (OIDPs) constitute a significant healthcare cost burden in the US and worldwide. Thus, their generic development and entry are being sought, yet regulatory methods/paths to assess bioequivalence have not yet been established, as blood drug levels do not necessarily reflect local lung actions, and no in vitro dissolution test has been shown to predict their clinical performance and pharmacokinetics as a bioequivalence demonstration. Hence, this corporative research agreement project with FDA will attempt to develop an in vitro dissolution test method for OIDPs, capable of predicting their pharmacokinetics (systemic exposure) in humans via semi-physiological lung deposition and disposition kinetics modeling using three different, investigational dry powder inhaler formulations of a poorly soluble inhaled corticosteroid, fluticasone propionate, currently being tested by FDA's Office of Generic Drugs.