Physiologically Based Biopharmaceutic Lung Deposition Modeling to Guide Clinical Device Transition of Protein A from...

Development Protein A (DPA) is a novel therapeutic biologic designed for inhaled administration. In phase I clinical studies, the DPA solution is administered using a continuous-output nebulizer. In subsequent studies, DPA is planned to be administered as a spray-dried powder formulation by using a dry powder inhaler (DPI). The implications for human drug product performance, such as regional lung dose, pharmacodynamic (PD), and pharmacokinetic (PK) parameters, when transitioning from a nebulizer to a DPI should be understood to maintain safety and efficacy. Here, we present a physiologically based biopharmaceutic modeling (PBBM) analysis linking in vitro and in vivo drug product performance. Specifically, PBBM is used to predict regional lung dose deposition from two early-stage drug products, namely, a continuous nebulizer and a DPI. The predictions were subsequently tested in a clinical PK bridging study, and the difference between nebulizer and DPI lung deposition patterns was used to investigate whether the total, central, or peripheral lung dose drives systemic exposure. To select clinical study doses, LungSim/GIsim, an AstraZeneca proprietary PBBM platform, was used to link device-metered dose to (regional) lung dose by simulating the interplay between lung morphology, inhalation maneuver, and in vitro-measured aerosol properties. DPA PK profiles were determined from healthy volunteers dosed on separate occasions using a nebulizer or a DPI. The total lung dose was predicted to be similar; however, the nebulizer was predicted to deposit the total lung dose more centrally in the lung compared to the DPI (which deposits more peripherally). Since the predicted total lung dose and observed PK parameters are comparable between the DPI and nebulizer, we suggest that systemic exposure and C_max are driven by the total lung dose and that changes to aerosol properties are unlikely to impact PK parameters as long as the total lung dose remains unchanged. Consequently, the presented PBBM analysis can help anticipate the impact of early-stage aerosol property changes on lung dose and PK parameters. As development progresses, additional critical product attributes are determined and PD parameters investigated, which need to be incorporated into the PBBM analysis and thus linked to previously established relationships between the drug product, PK, and PD. When taken together, the overall knowledge can be used to support science and risk-based approaches during pharmaceutical development. This could include, but is not limited to, avoiding unnecessary PK and PD bridging studies between clinical phases, which could accelerate the availability of novel drug products for patients.