Inhalation delivery dramatically improves the efficacy of topotecan for the treatment of local and distant lung cancer.

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.

• Authors: Philip J Kuehl, Christin M Yingling, Devon Dubose, Michael Burke, David A Revelli, Wenshu Chen, Wendy W Dye, Steven A Belinsky, Mathewos Tessema
• Journal: Drug delivery (Drug Deliv) Vol. 28 Issue 1 Pg. 767-775 (Dec 2021) ISSN: 1521-0464 [Electronic] England
• PMID: 33860729 (Publication Type: Journal Article)

Chemical References

• KRAS protein, human
• Topoisomerase I Inhibitors
• Topotecan
• Proto-Oncogene Proteins p21(ras)

Topics

• Administration, Inhalation
• Animals
• Antineoplastic Combined Chemotherapy Protocols
• Cell Line, Tumor
• Chemistry, Pharmaceutical
• Genes, erbB-1 (genetics)
• Half-Life
• Humans
• Lung Neoplasms (drug therapy)
• Metabolic Clearance Rate
• Proto-Oncogene Proteins p21(ras) (genetics)
• Rats
• Rats, Sprague-Dawley
• Topoisomerase I Inhibitors (administration & dosage, pharmacokinetics, pharmacology)
• Topotecan (administration & dosage, pharmacokinetics, pharmacology)
• Tumor Burden
• Xenograft Model Antitumor Assays