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Glenn Noronha, Prokash Paul, Barrett Katz, Nathan Teuscher; PK model with concentration-dependent clearance for zuretinol acetate, an oral agent in development for treatment of inherited retinal dystrophy caused by LRAT or RPE65 mutations. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4942.
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Zuretinol acetate (ZA) is an ester prodrug of 9-cis-retinol under development for the treatment of subjects with inherited retinal dystrophy (IRD) caused by mutations in LRAT or RPE65, which result in an inability to cycle 11-cis-retinal in the visual cycle. The active, 9-cis-retinol, can participate in the visual cycle, gets oxidized to 9-cis-retinal and replaces deficient 11-cis-retinal through formation of isorhodopsin, an analog of endogenous chromophore rhodopsin, formed when 11-cis-retinal forms a reversible complex with opsin. Deficiency in 11-cis-retinal, inability to produce rhodopsin, and therefore complete the visual cycle, results in compromised visual function, progressing eventually to blindness. In this analysis, pharmacokinetic (PK) data of 9-cis-retinol were explored and a population PK model was developed to describe the concentration-time profile for 9-cis-retinol following oral administration of ZA
Non-linear mixed effects modeling was used to develop a structural PK model for 9-cis-retinol concentrations in plasma following oral administration of ZA. 9-cis-retinol concentrations from 4 clinical studies (2 studies in healthy volunteers and 2 studies in subjects with IRD caused by LRAT or RPE65 mutations) were combined into a single analysis dataset. Standard population PK modeling methods were utilized to select an optimal model for observed concentrations.
The population PK model for 9-cis-retinol following oral administration of ZA yielded zero-order absorption, suggestions of a 2-compartment disposition and a saturable clearance mechanism that approached zero at low 9-cis-retinol concentrations. The dependence of drug clearance on 9-cis-retinol concentrations accurately captures and is consistent with low levels of 9-cis-retinol observed up to 30 days after a single dose of ZA
The population PK model for 9-cis-retinol following oral administration of ZA includes a unique feature of concentration-dependent clearance that approaches zero at low concentrations of 9-cis-retinol. Models such as 3-compartment disposition models did not adequately fit the concentration-time profiles for 9-cis-retinol. This unique finding suggests that there may be recycling of 9-cis-retinol to afford protection of the visual cycle as an adaptive protection for preservation of vision.
This is a 2020 ARVO Annual Meeting abstract.
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