Pulmonary and renal tolerance of cisplatin-based regimens combining intravenous and endotracheal routes for lung cancer treatment in mice

• Published in: International journal of pharmaceutics Vol. 599; p. 120425
• Main Authors: Chraibi, S., Rosière, R., De Prez, E., Antoine, M.H., Remmelink, M., Langer, I., Nortier, J., Amighi, K., Wauthoz, N.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15-04-2021
• Subjects: bronchoalveolar lavage fluid (BALF); Cystatin c; Macrophages; Neutrophil-gelatinase associated lipocalin (NGAL); Polymorphonuclear neutrophils; Pro-inflammatory cytokines; Pro-inflammatory cytokines; bronchoalveolar lavage fluid (BALF); Macrophages; Cystatin c; Polymorphonuclear neutrophils; Neutrophil-gelatinase associated lipocalin (NGAL)
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2021.120425

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•At MTD, CIS-DPI was better tolerated than an IV administration of cisplatin solution.•Adding CIS-DPI to CIS-IV at their respective MTD increased inflammation biomarkers.•Decreasing CIS-IV dose by 25% in combinations improved pulmonary and renal tolerance.•Staggering CIS-DPI administration from CIS-IV by 24 h improved the renal tolerance.
Despite recent advances, platinum-based chemotherapy (partially composed of cisplatin, CIS) remains the backbone of non-small-cell lung cancer treatment. As CIS presents a cumulative and dose-limiting nephrotoxicity, it is currently administered with an interruption phase of 3–4 weeks between treatment cycles. During these periods, the patient recovers from the treatment side effects but so does the tumour. Our strategy is to increase the treatment frequency by delivering a cisplatin controlled-release dry powder for inhalation (CIS-DPI) formulation during these off-cycles to expose the tumour environment for longer to CIS, increasing its effectiveness. This is promising as long as the pulmonary and renal toxicities remain acceptable. The aim of the present investigation was to evaluate the pulmonary and renal tolerance of CIS-DPI (three times per cycle) and CIS using the intravenous (IV) route (CIS-IV) (one time per cycle) as monotherapies and to optimize their combination in terms of dose and schedule. At the maximum tolerated dose (MTD), combining CIS-DPI and CIS-IV impaired the pulmonary and the renal tolerance. Therefore, pulmonary tolerance was improved when the CIS-IV dose was decreased by 25% (to 1.5 mg/kg) while maintaining the MTD for CIS-DPI. In addition to this dose adjustment, a delay of 24 h between CIS-DPI and CIS-IV administrations limited the acute kidney injury.