The Preclinical Safety, Toxicity and Pharmacokinetics (Pk) of Targeted Episcleral Delivery of Topotecan (TPT), Melphalan (MEL) and Its Combination with Dexamethasone (DEX)

Abstract

Purpose : To determine the preclinical safety, toxicity (TOX) and the Pk (ocular and plasma) of 0.3, 0.6, 0.9 mg of TPT, 0.9:3 mg of TPT:DEX, 0.3:3 mg of MEL-DEX or 0.6:3 mg of the MEL:DEX delivered by the targeted episcleral delivery system (TEDS).

Methods : New Zealand White rabbits (NZW) were assigned to TOX (n=5 per dose group) or PK (n=3 per time point at 1,2,7,14,21,28,42 or 56 days) groups and followed for at least 12 weeks by ocular exams, electroretinography (ERG), fundus photography. OD was implanted with the TEDS and OS used as control.
Globes were dissected in proximal (PROX) and distal (DIST) hemispheres, relative to the implant location. Choroid (cho), retina (ret), vitreous (vit) and plasma samples were analyzed by HPLC for drug content. Pk is reported as C_max (ng or gram per ml or gram), T_max, (day after dosing) and T_LC90 (days with conc. above retinoblastoma LC₉₀).

Results : TPT lactone (active isoform) was present at therapeutically relevant concentrations (C_max, T_max, T_>LC90) in ocular tissues as follows: 0.3-mg TPT (PROX cho: 2.7 ug/g, 2, 14; ret: 0.86 ug/g,2,14); 0.6-mg TPT (PROX cho: 10.6 ug/g,2,21; ret: 1.1 ug/g,1,21; vit: 8.2 ng/ml,21,1; and DIST ret: 50 ng/g,2,1; vit: 30 ng/ml,2,1); 0.9-mg TPT (PROX cho: 21.6 ug/g,2,21; ret: 2 ug/g,1,28; vit: 10.21 ng/ml, 21,1; and DIST cho: 166.23 ng/g,7,21; ret: 87.32 ng/g,7,21; vit: 5.72 ng/ml,21,1). 0.9:3-mg TPT:DEX (PROX cho: 52.12 ug/g,1,14; ret: 8.7 ug/g,1,7; vit: 21.7 ng/ml,1,1; and DIST cho: 151.6 ng/g,2,7; ret: 45.6 ng/g,1,2; vit: 12.1 ng/ml,1,2). After MEL:DEX delivery, the 0.3:3-mg dose yielded to therapeutic MEL concentration in the proximal choroid only on day 1 (130 ng/g) while the 0.6:3-mg dose showed it in the proximal choroid (1.7 ug/g,1,2) and retina (272 ng/g,1,7).
All groups demonstrated good systemic tolerability. In TPT-only TOX groups, serous retinal detachment was seen between days 7 and 21, resolving spontaneously, followed by choroidal vascular atrophy with dose-dependent intensity. There was non-specific partial decrease in ERG amplitude, particularly after 0.9-mg TPT. Neither TPT:DEX nor MEL:DEX produced similar findings

Conclusions : It was characterized the safety and Pk of topotecan, melphalan and combinations with dexamethasone, delivered by the TEDS, in support of its clinical development.for the treatment of retinoblastoma and uveal melanoma.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.