Safety and Tolerability of Topotecan-Eluting Radiopaque Microspheres for Hepatic Chemoembolization in a Rabbit Preclinical Model

• Published in: Cardiovascular and interventional radiology 2020-12, Vol.43 (12), p.1918-1924
• Main Authors: Mikhail, Andrew S., Levy, Elliot B., Krishnasamy, Venkatesh P., Woods, David L., Esparza-Trujillo, Juan A., Bakhutashvili, Ivane, Banovac, Filip, Wakim, Paul G., Negussie, Ayele H., Tang, Yiqing, Henman, Alexander, Willis, Sean L., Karanian, John W., Pritchard, William F., Lewis, Andrew L., Wood, Bradford J.
• Format: Article
• Language: English
• Subjects: Alanine; Alanine transaminase; Animals; Aspartate aminotransferase; Camptothecin; Carcinoma, Hepatocellular - diagnosis; Carcinoma, Hepatocellular - therapy; Cardiology; Chemoembolization; Chemoembolization, Therapeutic - methods; Elution; Embolization; Euthanasia; Fluoroscopy; Humans; Imaging; Irinotecan; Laboratory Investigation; Liver; Liver Neoplasms - diagnosis; Liver Neoplasms - therapy; Liver Neoplasms, Experimental - diagnosis; Liver Neoplasms, Experimental - therapy; Medicine; Medicine & Public Health; Metastases; Microspheres; Necropsy; Nuclear Medicine; Rabbits; Radiology; Radiopacity; Radiosensitizers; Topoisomerase I Inhibitors - pharmacology; Topotecan; Topotecan - pharmacology; Toxicity; Ultrasound
• ISSN: 0174-1551; 1432-086X
• DOI: 10.1007/s00270-020-02609-z

Purpose Topotecan is a camptothecin analogue with potential advantages over irinotecan for transarterial chemoembolization (TACE) of hepatic colorectal metastases including greater anti-neoplastic activity without enzymatic activation. The purpose of this study was to assess safety and tolerability of topotecan-loaded radiopaque microspheres (ROMTOP) administered by TACE in a rabbit model and to compare the in vitro elution of topotecan from microspheres to irinotecan. Materials and Methods Topotecan was loaded into radiopaque microspheres (70–150 µm, DC Bead LUMI™, Biocompatibles UK Ltd—Boston Scientific Corporation) to the maximum capacity of 80 mg/mL of microspheres. Six healthy New Zealand White rabbits underwent hepatic TACE with ROMTOP under fluoroscopic guidance until angiographic stasis. Assessment of toxicities included regular liver function tests and complete blood counts until euthanasia 28 days post-TACE. In vitro topotecan elution from the microspheres was assessed using an open-loop flow-through system and compared to irinotecan. Results The mean bead volume and topotecan dose delivered were 0.086 mL (0.076–0.105 mL) and 1.99 mg/kg (1.51–2.55 mg/kg), respectively. Aspartate aminotransferase and alanine aminotransferase were elevated post-embolization but resolved within 2 weeks. One rabbit died two days after TACE with pyloric duodenal perforation observed at necropsy, potentially due to non-target embolization. In vitro elution of topotecan from ROMTOP was complete in 10 h compared to 3 h for irinotecan-loaded microspheres. Conclusion Selective embolization with ROMTOP was tolerated at a dose of 2 mg/kg (24 mg/m 2 ) in rabbits. In vitro topotecan elution from microspheres was more prolonged compared to irinotecan.