ABSTRACT
The work led to the formulation of a powder of calcium phosphate coated liposomes containing cyclosporine A (CsA). The formulation was designed to reduce the dose of CsA to be administered following lung transplantation. Potentially this formulation can be used also to contain the inflammatory process due to SARS-CoV-2. Calcium phosphate (CaP) is a material found in bones and teeth and considered non-toxic and biocompatible and this coating could reduce the recognition by alveolar macrophages and increase the cell uptake. Moreover, CaP is insoluble at physiological pH (7.4), while it solubilizes easily at pH below 5. This could favor drug release in the cell after pinocytosis and in inflamed tissues, while reducing drug release at physiological pH [1]. The liposomes produced were evaluated in terms of size, surface charge and drug loading. The presence of the CaP coating was verified by calcium titration, variation of the zeta potential and by cryogenic transmission electron microscopy (cryo-TEM). The highest loading was obtained in the formulation containing CsA at 7% (w/w). Cholesterol was added to liposomes at two different concentrations in order to improve the stability of the nanostructure and reduce the drug leakage. However, cholesterol did not bring any improvement to the formulation. The inhalation powder produced by spray drying with the best aerosolization performance (fine particle fraction of coated liposomes powder 33.69 - 1.6% and 50.50- 0.6% for the uncoated liposomes powder) was obtained using a 1:3 weight ratio between liposomes and excipients using mannitol as bulking agent and 15% L-leucine. Key Message: This work aimed to develop a respirable dry powder for inhalation containing CsA for the local treatment of lung immune diseases. CsA was efficiently loaded into CaP-coated liposomes and transformed into a respirable powder by spray-drying. The inhaled immunosuppressive product would offer multiple advantages related to drug deposition at the target site. Furthermore, the coating of the liposomes governs the release of the drug which will occur only at only at biological acidic conditions.
ABSTRACT
Background. ADG20 is a fully human IgG1 monoclonal antibody engineered to have potent and broad neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and additional SARS-like CoVs with pandemic potential and an extended half-life. A QSP/PBPK model was constructed using ADG20-specific physiochemical properties and published non-human primate (NHP) and human PK data for other antibodies;it was used to a priori predict and confirm NHP and human PK. Methods. An existing QSP/PBPK model was modified to include 3 distinct lung sub-compartments: upper airway, lower airway, and alveolar tissue (Figure A). Each sub-compartment (Figure B) contained an epithelial lining fluid (ELF) space (Figure B). The model was fit separately to digitized NHP and human serum PK data for 7 extended half-life antibodies to estimate the apparent neonatal Fc receptor (FcRn) binding affinity (KD,FcRn) and bioavailability by drug. Nasopharyngeal swab (upper airway) and lung (lower airway) ELF PK data from 4 additional antibodies were used to optimize a single rate constant for transcytosis in lung. Patches of positive charge was a covariate on the rate of pinocytosis of antibody entry and exit from the endosomal space (Figure B). Observed NHP (ADG20 10 mg/kg IM) and human (ADG20 300 mg IM) PK data collected over the initial 21 days post dose were compared with model forecasts from a 1000-iteration simulation. Results. The distribution of fitted NHP KD,FcRn provided accurate predictions of NHP serum PK data (Figure C). NHP ADG20 KD,FcRn was optimized to be 35.7 nM and human ADG20 KD,FcRn (9.55 nM) was derived using a mean NHP:human KD,FcRn ratio of 3.74 across antibodies. Model-based simulated human serum PK data using inter-subject variability from NHP and actual weight distribution from an ongoing Phase 1 study aligned with initial 21-day data (Figure D). Using an adult CDC weight distribution (45-150 kg), the simulated median exceeded 74 days. Conclusion. The QSP/PBPK model a priori predicted NHP and human ADG20 PK. This innovative QSP-based modeling and simulation approach enabled the evaluation of candidate dose regimens prior to the availability of PK data, supporting the rapid advancement of the ADG20 clinical program during the COVID-19 pandemic.