Danicopan, an Oral Complement Factor D Inhibitor, Exhibits High and Sustained Exposure in Ocular Tissues in Preclinical Studies.

Autor:	Boyer DD; Alexion, AstraZeneca Rare Disease, New Haven, CT, USA., Ko YP; Alexion, AstraZeneca Rare Disease, New Haven, CT, USA., Podos SD; Alexion, AstraZeneca Rare Disease, New Haven, CT, USA., Cartwright ME; Alexion, AstraZeneca Rare Disease, New Haven, CT, USA., Gao X; Alexion, AstraZeneca Rare Disease, New Haven, CT, USA., Wiles JA; Alexion, AstraZeneca Rare Disease, New Haven, CT, USA., Huang M; Alexion, AstraZeneca Rare Disease, New Haven, CT, USA.
Jazyk:	angličtina
Zdroj:	Translational vision science & technology [Transl Vis Sci Technol] 2022 Oct 03; Vol. 11 (10), pp. 37.
DOI:	10.1167/tvst.11.10.37
Abstrakt:	Purpose: Complement alternative pathway (AP) dysregulation has been implicated in geographic atrophy, an advanced form of age-related macular degeneration. Danicopan is an investigational, first-in-class inhibitor of factor D, an essential AP activation enzyme. We assessed danicopan distribution to the posterior segment of the eye after oral dosing. Methods: Tissue distribution of drug-derived radioactivity was evaluated using whole-body autoradiography following oral administration of [14C]-danicopan to pigmented and albino rats. Pharmacokinetics and ocular tissue distribution were studied in pigmented and albino rabbits following single and multiple oral dosing of danicopan. The melanin binding property was characterized in vitro. Results: Radioactivity was distributed widely in rats and became nonquantifiable in most tissues 24 hours postdose except in the pigmented rat uvea (quantifiable 672 hours postdose). Danicopan binding to melanin was established in vitro. After single dosing, the maximum concentration (Cmax) and area under the curve (AUC) in neural retina and plasma were similar in both rabbit types. After multiple dosing, AUC in neural retina was 3.4-fold higher versus plasma in pigmented rabbits. Drug levels in choroid/Bruch's membrane (BrM)/retinal pigment epithelium (RPE) were similar to plasma in albino rabbits but higher in pigmented rabbits: Cmax and AUC were 2.9- and 23.8-fold higher versus plasma after single dosing and 5.8- and 62.7-fold higher after multiple dosing. In pigmented rabbits, ocular tissue exposures slowly declined over time but remained quantifiable 240 hours postdose. Conclusions: The results demonstrate that danicopan crosses the blood-retina barrier and binds melanin reversibly, leading to a higher and more sustained exposure in melanin-containing ocular tissues (choroid/BrM/RPE) and in the neural retina as compared to in plasma after repeated oral dosing in pigmented animals. Translational Relevance: These findings suggest that oral danicopan possesses potential for treating geographic atrophy because AP dysregulation in the posterior segment of the eye is reported to be involved in the disease pathogenesis.
Databáze:	MEDLINE
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