September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
The Preclinical Safety, Toxicity and Pharmacokinetics (Pk) of Targeted Episcleral Delivery of Topotecan (TPT), Melphalan (MEL) and Its Combination with Dexamethasone (DEX)
Author Affiliations & Notes
  • Ricardo A P De Carvalho
    3T Ophthalmics, Irvine, California, United States
    3T Biopolymers, Sao Paulo, Brazil
  • Pamela P Ko
    3T Ophthalmics, Irvine, California, United States
    Eye Care for Animals, San Diego, California, United States
  • A. Linn Murphree
    Childrens Hospital of Los Angeles, USC, Los Angeles, California, United States
  • robert brito
    3T Ophthalmics, Irvine, California, United States
  • Jonathan Moreno
    3T Ophthalmics, Irvine, California, United States
  • Paulin N Wahjudi
    3T Ophthalmics, Irvine, California, United States
  • Monica C Vargas-Dougherty
    3T Ophthalmics, Irvine, California, United States
  • Claudia Mendes
    3T Biopolymers, Sao Paulo, Brazil
  • Guilherme C Matsutani
    3T Biopolymers, Sao Paulo, Brazil
  • Jacques Manders
    3T Ophthalmics, Irvine, California, United States
  • Footnotes
    Commercial Relationships   Ricardo De Carvalho, 3T Ophthalmics (I), 3T Ophthalmics (E), 3T Ophthalmics (P), 3T Ophthalmics (S); Pamela Ko, 3T Ophthalmics (F); A. Linn Murphree, 3T Ophthalmics (P); robert brito, 3T Ophthalmics (E); Jonathan Moreno, 3T Ophthalmics (E); Paulin Wahjudi, 3T Ophthalmics (E); Monica Vargas-Dougherty, 3T Ophthalmics (E); Claudia Mendes, 3T Biopolymers (E); Guilherme Matsutani, 3T Biopolymers (E); Jacques Manders, 3T Ophthalmics (E)
  • Footnotes
    Support  Brazil Innovation Agency (FINEP)
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 4007. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Ricardo A P De Carvalho, Pamela P Ko, A. Linn Murphree, robert brito, Jonathan Moreno, Paulin N Wahjudi, Monica C Vargas-Dougherty, Claudia Mendes, Guilherme C Matsutani, Jacques Manders; The Preclinical Safety, Toxicity and Pharmacokinetics (Pk) of Targeted Episcleral Delivery of Topotecan (TPT), Melphalan (MEL) and Its Combination with Dexamethasone (DEX). Invest. Ophthalmol. Vis. Sci. 2016;57(12):4007.

      Download citation file:


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

      ×
  • Supplements
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 Cmax (ng or gram per ml or gram), Tmax, (day after dosing) and TLC90 (days with conc. above retinoblastoma LC90).

Results : TPT lactone (active isoform) was present at therapeutically relevant concentrations (Cmax, Tmax, 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.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×