Pharmacokinetics, Toxicities, and Vascular Variations in a Small Animal (Rabbit) Model of Intra-arterial Chemotherapy

Abstract

Purpose : We recently described the first small animal model of intra-arterial chemotherapy (IAC) in rabbits. Here, we determine the pharmacokinetics of IAC melphalan in this model, and the systemic and ocular toxicities associated with IAC melphalan. We also describe, for the first time, the vascular variations in ocular blood supply in rabbits.

Methods : Ocular vascular supply was determined angiographically in 79 eyes of 47 3.0kg-New Zealand white rabbits. The dominant ophthalmic artery (OA) of each eye was selectively catheterized. Melphalan 0.4mg/mL (up to 1.2mg/kg) was infused in pulsatile fashion. For pharmacokinetic studies, 18 rabbits were sacrificed at serial time-points. Retina, bilateral vitreous, and blood were collected. Toxicity was assessed by fluorescein angiography, electroretinography, and histopathology, prior to and 5-weeks post-treatment. Complete blood counts were obtained weekly.

Results : The OA was successfully catheterized for 79/79(100%) eyes in 47/47(100%) rabbits. Melphalan was delivered in 31/31(100%) eyes. External OA-dominant vascular variation was present in >75% of eyes, and dual internal/external supply in ~5%, with no correlation between a rabbit's two eyes. In treated eyes, maximum melphalan concentration (C_max) in retina was 4.95µM (30-minutes post-infusion) vitreous C_max was 2.24µM (1-hour), and areas-under-the-curve (AUC_0→∞) were 5.26µM*hr for retina and 4.19µM*hr for vitreous. Peripheral blood C_max was 1.04µM. Drug half-life was ~1 hour. Treated eye vitreous C_max was >100-fold higher, and AUC_0→∞ was ~50-fold higher, than untreated eye. No angiographic or histopathologic evidence of vascular occlusion, emboli, or retinal damage were seen, even with 1.2mg/kg melphalan. Electroretinographic reductions were not seen 5 weeks following IAC melphalan treatment. With 0.8-1.2mg/kg melphalan, transient neutropenia occurred at 1-week, which was not seen with 0.4mg/kg doses.

Conclusions : This is the first small animal model of IAC. Ocular vascular supply in the rabbit is variable, and is independent for each eye. IAC melphalan delivery in rabbits leads to excellent ocular penetration and pharmacokinetics, with peak vitreous drug concentrations and areas-under-the-curve that are significantly better than in previous large animal models of IAC. IAC melphalan did not lead to significant ocular, vascular, or systemic toxicities in our rabbit model system.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.