Novagali Pharma SA, Evry, France.
J Ocul Pharmacol Ther. 2013 Mar;29(2):258-69. doi: 10.1089/jop.2012.0044. Epub 2013 Jan 18.
Dexamethasone palmitate (DXP) is a lipophilic prodrug of dexamethasone (DXM), a potent corticosteroid used to treat a variety of ophthalmic diseases. The aim of the study was to characterize the sustained release capacity (in rabbit), efficacy (in rat and rabbit), and safety (in rabbit, cat, and minipig) of intravitreal (IVT) DXP emulsions in preclinical models.
Oil-in-water emulsions of DXP were administered by IVT injections in rats, rabbits, cats, or minipigs. Efficacy was assessed in rabbits by the inhibition of VEGF-induced vascular leakage and in rats by inhibition of laser-induced choroidal neovascularization. Concentrations of DXP and DXM in aqueous humor, vitreous, retina, choroid, and blood were determined to characterize the ocular and systemic pharmacokinetic (PK) profile. Complete ophthalmic examinations (indirect ophthalmoscopy, slit-lamp biomacroscopy, electroretinography, tonometry) were performed to assess the ocular safety of IVT DXP doses up to 2,600 μg in minipig, followed by histopathologic examinations. A validated feline model of DXM-induced elevated intraocular pressure (IOP) was used to assess the ocular hypertensive impact (i.e., the safety) of an IVT injection of DXP emulsion.
Rat and rabbit efficacy data demonstrated that IVT injections of DXP emulsions were effective. Rabbit PK data demonstrated that following a single 1,280 μg IVT injection resulted in sustained DXM levels in the retina and choroid (1,179.6 and 577.7 ng/g with a half-life of 189 and 103 days, respectively) sufficient to inhibit VEGF-induced vascular hyper-permeability for up to 9 months. No adverse ocular findings were observed in the rabbit at the 1,280 μg DXP dose. Plasma levels of DXP and DXM were close to the lower limit of quantification (0.5 ng/mL). In minipigs, no systemic effects were observed at a dose up to 2,600 μg DXP. In steroid responsive cats, IVT DXP emulsions increased IOP to a lesser extent than triamcinolone acetonide with a more rapid return to basal levels and no evidence of cataract formation.
IVT injections of DXP emulsions were well tolerated and shown to be efficacious for the sustained release of the drug, with the potential to control vascular leakage up to 9 months following a single IVT injection. These data suggest that IVT injections of DXP emulsions could be a safe and effective alternative IVT drug delivery vehicle for corticosteroid to treat back of the eye diseases complicated by macular edema.
棕榈酸倍他米松（DXP）是一种具有生物利用度的地塞米松（DXM）前药，地塞米松是一种强效皮质类固醇，用于治疗多种眼部疾病。本研究旨在通过临床试验模型，研究玻璃体内（IVT）DXP 乳剂的持续释放能力（在兔）、疗效（在大鼠和兔）和安全性（在兔、猫和小型猪）。
通过 IVT 注射向大鼠、兔子、猫或小型猪施用 DXP 的油包水乳剂。通过抑制 VEGF 诱导的血管渗漏评估兔子的疗效，通过抑制激光诱导的脉络膜新生血管化评估大鼠的疗效。通过测定房水、玻璃体液、视网膜、脉络膜和血液中的 DXP 和 DXM 浓度，描述眼部和全身药代动力学（PK）特征。在小型猪中，进行了完整的眼科检查（间接检眼镜、裂隙灯生物显微镜、视网膜电图、眼压计），以评估 IVT DXP 剂量高达 2600μg 的眼部安全性，随后进行组织病理学检查。使用经验证的猫 DXM 诱导的眼内压升高模型来评估 IVT 注射 DXP 乳剂对眼高压的影响（即安全性）。
大鼠和兔子的疗效数据表明 IVT 注射 DXP 乳剂是有效的。兔子的 PK 数据表明，单次 1280μg IVT 注射后，视网膜和脉络膜中的 DXM 水平持续（半衰期分别为 189 天和 103 天，分别为 1179.6 和 577.7ng/g）足以抑制 VEGF 诱导的血管高通透性长达 9 个月。在 1280μg DXP 剂量下，兔子未观察到眼部不良发现。血浆中 DXP 和 DXM 水平接近定量下限（0.5ng/mL）。在小型猪中，高达 2600μg DXP 剂量下未观察到全身作用。在对类固醇有反应的猫中，IVT DXP 乳剂引起的眼压升高程度低于曲安奈德，且眼压恢复到基础水平的速度更快，且无白内障形成的证据。
IVT 注射 DXP 乳剂具有良好的耐受性，并显示出对药物持续释放的疗效，单次 IVT 注射后，有潜力控制血管渗漏长达 9 个月。这些数据表明，IVT 注射 DXP 乳剂可能是一种安全有效的替代 IVT 皮质类固醇药物输送载体，用于治疗伴有黄斑水肿的眼底疾病。
