Biopharmaceutics of (R)-roscovitine by Inhalation

Magda Swedrowska¹, Zachary Enlo-Scott¹, Laurent Meijer² & Ben Forbes¹

¹Institute of Pharmaceutical Science, King’s College London,150 Stamford Street, London SE1 9NH, UK

²ManRos Therapeutics, Centre de Perharidy, Roscoff, 29680, France

Summary

A novel therapeutic agent (R)-roscovitine is under investigation for delivery by inhalation for the treatment of cystic fibrosis. Inhaled therapy has the potential to reduce systemic side effects, enhance drug availability (lower doses may be required for optimal effect) by delivering a drug directly to the target organ. However, the pharmacokinetics and safety of (R)-roscovitine after delivery to the lungs by inhalation have not yet been evaluated. This study aims to assess the biocompatibility and permeability of (R)-roscovitine in a human airway epithelial cell line to provide a preliminary non-clinical evaluation of the drugs inhalation biopharmaceutics before further testing using an isolated perfused lung (IPL) model. The bronchial epithelial cell line, Calu-3 was used as an absorption model. Different concentrations of (R)-roscovitine (up to 250 µM, exposure for 24 h) were evaluated for biocompatibility using the MTT assay. The absorptive transport of (R)-roscovitine (100 and 280 µM) was evaluated across polarised epithelial cell layers with the transepithelial electrical resistance (TEER) was measured to ensure the integrity of the cell monolayer. (R)-Roscovitine showed a moderate dose-dependent reduction of the metabolic activity of Calu-3 cells, but the half maximal inhibitory concentration (IC50) was not reached at the concentrations tested. There was no significant difference in the absorptive transport between 100 and 280 µM (R)-roscovitine (P_app = 5.6 ± 0.56 and 5.9 ± 0.72 × 10^-5 cm/s, respectively) and TEER was not affected by the 2 h transport experiment. Based on physicochemical properties and the absorptive permeability of (R)-roscovitine in the Calu-3 respiratory epithelial cell drug transport model, the molecule is expected to be rapidly absorbed from the lungs. Further investigations will be performed using the IPL model.