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Jacques Manders, Jonathan Moreno, robert brito, Monica C Vargas-Dougherty, Pamela P Ko, Claudia Mendes, Guilherme C Matsutani, Ricardo A P De Carvalho; Selective Episcleral Drug Delivery of Neuroprotective Drugs. Toxicokinetics of a Neuroprotective Estradiol Analog and Implications for Treatment of Traumatic and Neurodegenerative Ocular Conditions. Invest. Ophthalmol. Vis. Sci. 2016;57(12):No Pagination Specified.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate the pre c l i n i c a l safety and pharmacokinetics of selective episcleral delivery of 3 mg and 6 mg doses of a molecule with previously demonstrated neuroprotective activity—17β-estradiol derivative with a lipophilic electron-donating adamantyl on the A-ring (NP4565)—formulated in the targeted-transscleral delivery systems (TTDS). Ex vivo diffusion were carried out using rabbit sclera to evaluate permeability and diffusion pattern in sclera.
Toxicity (n=5) and pharmacokinetics (n=3) of rabbits implanted unilaterally with TTDS. The PK group was euthanized at 24, 48 hour, 7, 14, 21, 28, 42, 56, 83 day. Ocular tolerability and toxicity were assessed by ocular examination, tonometry, and (ERG) for 12 weeks. OS was used as control. Plasma, ocular tissues (distal and proximal sections) were assayed by MS. For diffusion Franz chambers (n=6) were used with NP-0545 separated by rabbit sclera and maintained at 37°C for 24 hours.
A 3-mg dosing NP-4565 peaked in the proximal retina (C Max =372.36 ng/g, ±325.1) at 24 hrs and was l present at therapeutic concentrations on day 83 (C d83=70.3 ng/g, ±62.96). A 6-mg dosing, NP-4565 reached 33.94 ng/g ±14.3 on day 1, peaked in the proximal retina (Cmax=5.3 ug/g ±4.5) on day 2, and was detected on day 56 (Cd56=325 ng/g ±291). Ocular findings were mild and localized conjunctival reaction. Therapeutic concentrations (> 5 ng/gram) were found in the retina to day 83 and it was not detectable in the plasma at any time point. ERG did not reveal any significant changes. At 6-mg dose a slight trend towards an overall decrease in the sensitivity was observed. No difference in IOP was noted. Ex vivo diffusion of NP4565 showed a concentration-gradient driven diffusion pattern where by 24 hours approximately 5% of the total dosed NP-0545 had been recovered.
NP4565, a neuroprotective estradiol analog without hormonal activity, can be safely delivered from the TTDS in a sustained fashion and diffuse through the sclera and choroid to provide postulated neuroprotective concentrations to the retina as soon as on day 1 for at least 12 weeks. Clinical studies will evaluate its clinical safety and efficacy in mitigating photoreceptor and ganglion cell loss in neurodegenerative processes associated with traumatic and non-traumatic events.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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