Evaluation of Tumour Exposure following the Administration of an Innovative Cisplatin Dry Powder for Inhalation at Different Dose Levels and Regimens  

1. Wauthoz¹, S. Chraibi¹, T. Davenne^1,2, P. Gérard², R. Rosière^1,2, K. Amighi¹

¹ Unit of Pharmaceutics and Biopharmaceutics, Université libre de Bruxelles (ULB), boulevard du Triomphe, Campus plaine CP207, 1050 Brussels, Belgium – Nathalie.wauthoz@ulb.be

²  InhaTarget Therapeutics, Rue Antoine de Saint Exupéry 2, 6041 Gosselies, Belgium

Summary

Introduction. A cisplatin-based dry powder for inhalation (CIS-DPI-50) was developed to be administered during the off-cycles of conventional anticancer therapies to intensify tumour exposition to chemotherapy. The aim was to evaluate the exposure of lung tumour and organs to platinum after CIS-DPI-50 administration in lung tumour-bearing mice. Methods.  Pharmacokinetic and biodistribution studies were conducted following different cisplatin dose levels and regimens in the LLC1-Luc model. Results. After a single administration of CIS-DPI-50 at 0.5 mg/kg, platinum concentrations in the lung tumour were immediately high and increased slowly until reaching C_max 2h later (20 ± 17 ng/mg) before decreasing gradually. This led to an AUC_0-∞ of 10,683 ± 5,837 ng.min.mg^-1 in the lung tumour, which was nearly 10-fold higher than the AUC_0-∞ in tumour-free lungs (1,072 ± 825 ng.min.mg^-1). This trend was also observed at different dose levels and regimens within a week with platinum concentration in the lung tumour 2-fold (with 0.5 mg/kg/day x 3 days), 4-fold (with 0.5 mg/kg/day x 5 days) and up to 6-fold higher (with 1 mg/kg/day x 5 days) than in tumour-free lungs. Moreover, it seemed that the higher the weekly dose was, the higher the concentration in the lung tumour, which tended to demonstrate a higher penetration within the lung tumour than in tumour-free lungs due to a diffusion effect based on the gradient of concentration. Conclusion. Single and repeated CIS-DPI-50 induced a high lung tumour exposition without accumulation within the 1-week treatment.

Key Message

An innovative cisplatin-based dry powder for inhalation developed for the off-cycles of conventional anticancer therapies increases lung tumour exposure to platinum as revealed by pharmacokinetic and biodistribution data generated in the LLC1-Luc lung carcinoma model without accumulation within the 1-week treatment.