Modeling of corneal and retinal pharmacokinetics after periocular drug administration
Modeling of corneal and retinal pharmacokinetics after periocular drug administration
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DOI：
10.1167/iovs.07-0593
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发表时间：
2008-01-01
影响因子：
4.4
通讯作者：
Kompella, Uday B.
中科院分区：
文献类型：
--
作者：
Amrite, Aniruddha C.;Edelhauser, Henry F.;Kompella, Uday B.
目的。目的建立眼周(结膜下或后结膜下)给药后亲脂小分子在角膜和视网膜中的药代动力学模型。方法：对布朗-挪威(BN)大鼠眼周给药3 mg塞来昔布(一种选择性COX-2抑制剂)后的角膜和视网膜数据进行室内药代动力学分析。采用伯克利-麦当娜(Berkeley Madonna)微分差分式建模软件进行药物动力学建模。利用回归系数和Akaike信息准则(AIC)将数据拟合到具有一阶输入和配置的不同房室模型中，选择最优模型。这些模型是通过使用先前在Spraogue-Dawley(SD)大鼠中进行的研究中的塞来昔布数据进行验证的。该模型与泼尼松龙2.61mg2·61mg2·61 mg在白兔体内的角膜模型比较吻合，在其他两种剂量(0.261 mg和26.1mg泼尼松龙)下的角膜模型也得到验证。结果：塞来昔布在BN大鼠角膜中的药代动力学符合二室模型(眼周间隙和角膜，眼周制剂为溶解步骤)，并平行地从角膜和眼周间隙消除。与两室模型相比，加入分配室或塞来昔布混悬液的溶出步骤并没有导致角膜数据拟合的总体改善。对于增强适合度和解释角膜平面明显没有增加阶段的更重要的参数是包含从眼周间隙到角膜前区域的初始剂量回漏。该模型预测的塞来昔布浓度与SD大鼠角膜的实测值也有很好的相关性(r=0.99)。相似的药代动力学模型解释了药物在大鼠和兔动物模型中的角膜释放。眼周给药后视网膜药物动力学可用四室模型(眼周间隙、脉络膜转移室、视网膜和分配室)解释，并从眼周间隙、视网膜和脉络膜室消除。在药物可用于吸收或消除之前包括溶出-释放步骤，更好地解释了视网膜t(Max)。BN大鼠(r=0.99)和SD大鼠(r=0.99)在相同的模型中均能很好地拟合视网膜塞来昔布，但参数估计不同。结论眼周给药后亲脂小分子在角膜和视网膜中的药代动力学可用房室模型描述。模型分析表明：(1)从给药部位的渗漏很可能导致角膜浓度明显缺乏增加时相；(2)通过结膜或眼周血液和淋巴系统的消除显著有助于眼周给药后的药物清除；(3)小分子亲脂分子在大鼠和兔身上的角膜药代动力学可用类似的模型来解释；(4)尽管有色素和无色素的大鼠之间存在一些视网膜药代动力学参数的差异，但这些差异的生理学基础尚未确定。
PURPOSE. To develop pharmacokinetics models to describe the disposition of small lipophilic molecules in the cornea and retina after periocular (subconjunctival or posterior subconjunctival) administration.METHODS. Compartmental pharmacokinetics analysis was performed on the corneal and retinal data obtained after periocular administration of 3 mg of celecoxib (a selective COX-2 inhibitor) to Brown Norway (BN) rats. Berkeley Madonna, a differential and difference equation-based modeling software, was used for the pharmacokinetics modeling. The data were fit to different compartment models with first-order input and disposition, and the best fit was selected on the basis of coefficient of regression and Akaike information criteria (AIC). The models were validated by using the celecoxib data from a prior study in Sprague-Dawley (SD) rats. The corneal model was also fit to the corneal data for prednisolone at a dose of 2.61 mg in albino rabbits, and the model was validated at two other doses of prednisolone (0.261 and 26.1 mg) in these rabbits. Model simulations were performed with the finalized model to understand the effect of formulation on corneal and retinal pharmacokinetics after periocular administration.RESULTS. Celecoxib kinetics in the BN rat cornea can be described by a two-compartment (periocular space and cornea, with a dissolution step for periocular formulation) model, with parallel elimination from the cornea and the periocular space. The inclusion of a distribution compartment or a dissolution step for celecoxib suspension did not lead to an overall improvement in the corneal data fit compared with the two-compartment model. The more important parameter for enhanced fit and explaining the apparent lack of an increase phase in the corneal levels is the inclusion of the initial leak-back of the dose from the periocular space into the precorneal area. The predicted celecoxib concentrations from this model also showed very good correlation (r = 0.99) with the observed values in the SD rat corneas. Similar pharmacokinetics models explain drug delivery to the cornea in rat and rabbit animal models. Retinal pharmacokinetics after periocular drug administration can be explained with a four-compartment (periocular space, choroid-containing transfer compartment, retina, and distribution compartment) model with elimination from the periocular space, retina, and choroid compartment. Inclusion of a dissolution-release step before the drug is available for absorption or elimination better explains retinal t(max). Good fits were obtained in both the BN (r = 0.99) and SD (r = 0.99) rats for retinal celecoxib using the same model; however, the parameter estimates differed.CONCLUSIONS. Corneal and retinal pharmacokinetics of small lipophilic molecules after periocular administration can be described by compartment models. The modeling analysis shows that (1) leak-back from the site of administration most likely contributes to the apparent lack of an increase phase in corneal concentrations; (2) elimination via the conjunctival or periocular blood and lymphatic systems contributes significantly to drug clearance after periocular injection; (3) corneal pharmacokinetics of small lipophilic molecules can be explained by using similar models in rats and rabbits; and (4) although there are differences in some retinal pharmacokinetics parameters between the pigmented and nonpigmented rats, the physiological basis of these differences has yet to be ascertained.