Inhalation delivery dramatically improves the efficacy of topotecan for the treatment of local and distant lung cancer. (1st January 2021)

• Record Type: Journal Article
• Authors: Kuehl, Philip J.; Yingling, Christin M.; Dubose, Devon; Burke, Michael; Revelli, David A.; Chen, Wenshu; Dye, Wendy W.; Belinsky, Steven A.; Tessema, Mathewos
• Is Part Of: Drug delivery. Volume 28:Number 1(2021)
• Page Start: 767
• Page End: 775
• Publication Date: 2021-01-01
• Subjects: Topoisomerase inhibitor -- chemotherapy -- non-small cell lung cancer -- inhalation therapy -- dry powder -- aerosol -- KRAS -- EGFR mutant; Drug delivery systems -- Periodicals; Drug targeting -- Periodicals; 615.05
• DOI: 10.1080/10717544.2021.1912209
• Languages: English
• ISSNs: 1071-7544

Abstract

Abstract: Topotecan is potent anti-cancer drug approved for various malignancies but hematopoietic toxicities undermine its wider application and use of its most effective dose. This study aims to improve these limitations through inhalation-delivery. The pharmacokinetics, efficacy, and toxicity of 2–5 times lower inhalation doses of topotecan dry-powder were compared with the standard intravenous (IV) delivery once/twice-a-week. Human-derived EGFR-mutant (H1975), KRAS-mutant (A549), and EGFR/KRAS wild-type (H358) orthotopic and distant lung tumors were evaluated in murine models. Inhalation of 1 mg/kg topotecan significantly improved the half-life and drug exposure (area under the curve, AUC) compared to 5 mg/kg via IV-delivery. AUCs (h*ng/mL) for inhaled/IV topotecan in plasma, lung, liver, and brain were, 831/888, 60, 000/1080, 8380/4000, and 297/15, respectively; while the half-life was also greatly increased in these tissues. The average lung tumor burden of H358-derived tumors was reduced from 15.0 g to 8.4 g (44%) in rats treated once-a-week with 2 mg/kg IV and 1.8 g (88%) with 1 mg/kg inhaled topotecan, corroborating previous findings using A549- and H1975-derived orthotopic lung tumors. Importantly, inhaled topotecan showed superior efficacy in suppressing lung tumors at distant sites. The growth of H1975- and H358-derived subcutaneous xenografts were completely arrested and A549-derived tumors were significantly reduced in mice treated twice-a-week with 1 mg/kg inhaled topotecan compared to a minor (H1975 and H358) or no reduction (A549) with twice-a-week 5 mg/kg IV topotecan.