Orbital exposure of topotecan after ophthalmic artery chemosurgery in pigs: implications in disseminated retinoblastoma.

Abstract

Purpose : Orbital extension in retinoblastoma is frequent in developing countries and is a major cause of death. Despite multimodal therapy including high-dose chemotherapy, enucleation, and radiotherapy has improved life salvage, treatment is still associated with high toxicity. An alternative treatment strategy to improve clinical response would be to enhance chemotherapy delivery to the orbit and minimize systemic exposure. We aimed to study and compare the orbital exposure of topotecan after ophthalmic artery chemosurgery (OAC) and i.v infusion in an animal model.

Methods : Three landrace pigs received topotecan (4mg) 30-min OAC and samples were serially obtained from a peripheral artery and from a microdialysis probe inserted into the lateral rectus of the infused eye as a surrogate of the orbital vascular irrigation. Then, animals were recovered and after a wash-out period, plasma and microdialysate samples were collected after a 30-min i.v infusion of 4mg of topotecan. All samples were quantified by HPLC

Results : After OAC, animals reached a median topotecan exposure in the muscle sheath of 5624.3 ng*h/ml (AUC_m,OAC; range, 3922.3-12530.7) compared to only 23.2 ng*h/ml (AUC_m,iv; range, 18.0-74.9) after IV infusion of the drug. Thus, the median ratio of AUC_{m, OAC}/ AUC_m,iv was 218 (range, 75-540). Still, topotecan systemic exposure remained comparable between routes of drug delivery with median values of 141.2 ng*h/ml (AUC_pl,OAC; range, 126.9-191.4) and 138.7 ng*h/ml (AUC_pl,iv; range, 126.5-186.4) after OAC and IV infusion, respectively. Lastly, topotecan OAC was a much more selective route to reach the extraocular muscle than the systemic circulation as the median (range) muscle-to-plasma exposure ratio was 44.3 (27.8-65.5) after OAC compared to only 0.18 (0.13-0.4) after IV administration

Conclusions : OAC resulted in significantly higher topotecan exposure in the orbit of the pig compared to i.v infusion while similar systemic exposure was attained after both routes of drug delivery. Patients with orbital retinoblastoma may benefit from a multimodal treatment strategy including OAC therapy to control orbital tumor disease by increasing local drug exposure

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.