3:36 PM Abstract No. 231 Dose escalation study of topotecan-eluting radiopaque microspheres for hepatic chemoembolization in a rabbit preclinical model

Abstract

To evaluate the loading and elution of topotecan from radiopaque microspheres (ROMTOP) and determine the maximum dose that could be safely administered by transarterial chemoembolization in a rabbit preclinical model. All animal procedures were approved by the Animal Care and Use Committee. Topotecan elution from radiopaque microspheres (70-150 μm) was assessed in vitro using an open-loop flow-through system and compared to irinotecan. Rabbits underwent hepatic transarterial chemoembolization with topotecan-loaded radiopaque microspheres under fluoroscopic guidance until angiographic stasis. A 3+3 dose escalation study design was adopted to determine the maximum tolerated dose (MTD). Physical examination and behavioral assessment for adverse events were performed daily and liver function tests and complete blood counts were performed at regular intervals until euthanasia 28 days post chemoembolization. The maximum topotecan loading capacity in ROMTOP was 80 mg/mL. Complete drug elution of topotecan and irinotecan from microspheres took 10 and 3 hours in vitro, respectively, providing a direct comparison of topotecan to the better-characterized irinotecan. All rabbits survived for 28 days in the bland bead (dose: 0 mg/kg, N = 3) and low-dose (mean dose, 0.54 mg/kg, N = 3) cohorts. In the high-dose cohort (mean dose, 1.99 mg/kg, N = 6), one of six rabbits treated died two days after chemoembolization from pyloric duodenal perforation. All other rabbits survived for 28 days without dose limiting toxicity. An additional 5 rabbits were excluded from the study due to technical / procedural complications. No further dose escalation was possible as the maximum topotecan loading in the microspheres had been reached. Toxicity related to liver embolization with ROMTOP included alanine aminotransferase and aspartate transaminase elevations lasting 7-14 days. Embolization with ROMTOP was well tolerated up to a dose of 2 mg/kg, the maximum loading capacity of the microspheres. Topotecan may be an attractive candidate for local delivery via TACE with radiopaque drug-eluting microspheres due to its high potency and sustained drug release kinetics relative to irinotecan.