Inhalation delivery of topotecan is superior to intravenous exposure for suppressing lung cancer in a preclinical model

Intravenous (IV) topotecan is approved for the treatment of various malignancies including lung cancer but its clinical use is greatly undermined by severe hematopoietic toxicity. We hypothesized that inhalation delivery of topotecan would increase local exposure and efficacy against lung cancer while reducing systemic exposure and toxicity. These hypotheses were tested in a preclinical setting using a novel inhalable formulation of topotecan against the standard IV dose. Respirable dry-powder of topotecan was manufactured through spray-drying technology and the pharmacokinetics of 0.14 and 0.79 mg/kg inhalation doses were compared with 0.7 mg/kg IV dose. The efficacy of four weekly treatments with 1 mg/kg inhaled vs. 2 mg/kg IV topotecan were compared to untreated control using an established orthotopic lung cancer model for a fast (H1975) and moderately growing (A549) human lung tumors in the nude rat. Inhalation delivery increased topotecan exposure of lung tissue by approximately 30-fold, lung and plasma half-life by 5- and 4-folds, respectively, and reduced the maximum plasma concentration by 2-fold than the comparable IV dose. Inhaled topotecan improved the survival of rats with the fast-growing lung tumors from 7 to 80% and reduced the tumor burden of the moderately-growing lung tumors over 5- and 10-folds, respectively, than the 2-times higher IV topotecan and untreated control (<i>p</i>

静脉注射（IV）拓扑替康（topotecan）已获批用于包括肺癌在内的多种恶性肿瘤的治疗，但其严重的造血系统毒性极大限制了临床应用。本研究假设，吸入给药拓扑替康可提升其肺部局部暴露量与抗肺癌疗效，同时降低全身暴露与毒性反应。上述假设在临床前研究体系中得到验证：本研究以标准静脉给药剂量为对照，采用新型吸入式拓扑替康制剂开展实验。本研究通过喷雾干燥技术制备了可吸入式拓扑替康干粉，并对比了0.14 mg/kg、0.79 mg/kg两种吸入给药剂量与0.7 mg/kg静脉给药剂量的药代动力学特征。此外，本研究采用已建立的裸大鼠原位肺癌模型（分别针对快速生长型H1975与中等生长型A549人源肺肿瘤），对比了每周给药1次、共4次的1 mg/kg吸入给药拓扑替康与2 mg/kg静脉给药拓扑替康的疗效，并以未给药组作为对照。与等效静脉给药剂量相比，吸入给药可使肺组织中拓扑替康的暴露量提升约30倍，肺与血浆半衰期分别延长5倍与4倍，并使血浆峰浓度降低2倍。与剂量高出2倍的静脉给药拓扑替康组及未给药对照组相比，吸入给药拓扑替康可使快速生长型肺肿瘤裸大鼠的生存率从7%提升至80%，并使中等生长型肺肿瘤的肿瘤负荷分别降低5倍与10倍以上（*p*）。