Suprachoroidal Injection of Topotecan for Retinoblastoma: A Preclinical Study
Arun D Singh1, Vishal Raval2, Sandeep Kumar3
1Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland, Ohio.
Purpose:
To assess whether levels of topotecan that are expected to be therapeutic against retinoblastoma tumors can be achieved within the retina and choroid by suprachoroidal injection (SCI) and to assess toxicity and safety in vivo.
Design:
Pharmacokinetics and dose escalation toxicity study.
Subjects:
New Zealand white rabbits.
Methods:
In a pharmacokinetic study (N=18), aqueous, vitreous, retina, choroid, and plasma were separated and harvested serially (15, 30, 60, 120, and 360 minutes) following SCI. Topotecan (lactone) levels were measured and pharmacokinetic parameters were calculated. In the dose escalation toxicity study (N=8), toxicity was evaluated by ocular examination, fundus photography, OCT, full-field electroretinography (ffERG), and tissue histology. A single SCI of 50 μg/0.05 mL or two consecutive SCI totaling 100 μg/0.1 mL (N=4 rabbits per group) were administered.
Main Outcome Measures:
Topotecan (lactone) tissue levels and ocular toxicity (25% reduction in ffERG).
Results:
Following a single SCI of 50 μg topotecan, high levels of topotecan were achieved rapidly in both the retina and choroid. Retinal levels peaked by 15 minutes (12400±7336 ng/gm) followed by rapid decline to 2899±1361 ng/gm by 30 minutes, and then slower progressive decline that reached lowest levels at 360 minutes (469 ng/gm). Half-life (T1/2) in the retina was 24.8 minutes. Choroidal levels were 3.3-fold higher than retina with a similar rapid decline pattern. Vitreous level was highest at 15 min (278 ng/mL) with a slow progressive decline until 360 min (16.9 ng/ml). Plasma (mean 4.3±2.6 ng/ml) and aqueous (peak at 120 min, mean 87 ng/ml) levels remained low throughout the study. There were no signs of ocular toxicity or other adverse ocular events on either clinical examination, serial imaging studies, ffERG, or histology following sacrifice at 28 days.
Conclusions:
A single SCI of topotecan (50 μg/0.05 ml) achieved selective tissue distribution of its lactone moiety (retina/plasma, 1377.8) that was 23-fold higher than that reported with intraarterial chemotherapy (58.9) and more than 1000-fold higher than intravenous chemotherapy (1.32). These retinal levels were nontoxic and were 885-fold higher than the known topotecan IC50 for human retinoblastoma cells (IC50 14 ng/gm). Our findings support potential benefit of SCI of topotecan for patients with retinoblastoma.
Financial Disclosures:
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
