June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Pharmacokinetics, Toxicities, and Vascular Variations in a Small Animal (Rabbit) Model of Intra-arterial Chemotherapy
Author Affiliations & Notes
  • Anthony B Daniels
    Departments of Ophthalmology, Cancer Biology, and Radiation Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
    Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Michael T. Froehler
    Cerebrovascular Program, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Janene M. Pierce
    Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Amy H. Nunnally
    Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • M. Wade Calcutt
    Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, United States
  • Thomas M. Bridges
    Vanderbilt Center for Neurosciences Drug Discovery, Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, United States
  • David C. LaNeve
    Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Phillip E. Williams
    Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Kelli L. Boyd
    Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
    Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Michelle L. Reyzer
    Department of Biochemistry, Vanderbilt University, Nashville, Tennessee, United States
  • Craig W. Lindsley
    Vanderbilt Center for Neurosciences Drug Discovery, Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, United States
    Department of Chemistry, Vanderbilt University, Nashville, Tennessee, United States
  • Debra L. Friedman
    Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States
    Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Ann Richmond
    Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee, United States
    Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee, United States
  • Footnotes
    Commercial Relationships   Anthony Daniels, None; Michael Froehler, Blockade Medical (C), Medtronic (C), Medtronic (F), Microvention (F), Penumbra (F), Stryker (F); Janene Pierce, None; Amy Nunnally, None; M. Calcutt, None; Thomas Bridges, None; David LaNeve, None; Phillip Williams, None; Kelli Boyd, None; Michelle Reyzer, None; Craig Lindsley, None; Debra Friedman, None; Ann Richmond, None
  • Footnotes
    Support  This work was supported by a Career Starter Grant from the Knights Templar Eye Foundation [ABD], by the Vanderbilt Faculty Research Scholars program [ABD], by a Career Development Award from the Research to Prevent Blindness Foundation [ABD], and by an unrestricted departmental grant from Research to Prevent Blindness to the Vanderbilt Department of Ophthalmology and Visual Sciences. This work was also supported by grant NCI CA 116021 [AR] and by a Department of Veterans Affairs Career Scientist Award [AR]. It was also supported by P41 GM103391-06 and by the National Center for Research Resources, Grant UL1RR024975-01, now at the National Center for Advancing Translational Sciences (2 UL1 TR000445-06).
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 859. doi:
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    • Get Citation

      Anthony B Daniels, Michael T. Froehler, Janene M. Pierce, Amy H. Nunnally, M. Wade Calcutt, Thomas M. Bridges, David C. LaNeve, Phillip E. Williams, Kelli L. Boyd, Michelle L. Reyzer, Craig W. Lindsley, Debra L. Friedman, Ann Richmond; Pharmacokinetics, Toxicities, and Vascular Variations in a Small Animal (Rabbit) Model of Intra-arterial Chemotherapy. Invest. Ophthalmol. Vis. Sci. 2017;58(8):859.

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      © ARVO (1962-2015); The Authors (2016-present)

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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 (Cmax) in retina was 4.95µM (30-minutes post-infusion) vitreous Cmax was 2.24µM (1-hour), and areas-under-the-curve (AUC0→∞) were 5.26µM*hr for retina and 4.19µM*hr for vitreous. Peripheral blood Cmax was 1.04µM. Drug half-life was ~1 hour. Treated eye vitreous Cmax was >100-fold higher, and AUC0→∞ 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.

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