Deconvolution and IVIVC: Exploring the Role of Rate-Limiting Conditions.
Deconvolution and IVIVC: Exploring the Role of Rate-Limiting Conditions.
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DOI：
10.1208/s12248-015-9849-y
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Aarons L
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文献类型：
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作者：
Margolskee A;Darwich AS;Galetin A;Rostami-Hodjegan A;Aarons L
体外-体内相关性(IVCs)在制剂开发和药物审批中发挥着重要作用。IVIVC的核心是去卷积，这是一种得出体内“溶出度曲线”的方法，用于与体外溶出度数据进行比较。一般认为，以释放/溶解为速率限制步骤，IVIVCs可用于高渗透性和高可溶性化合物。在本文中，我们将传统的去卷积方法，Wagner-Nelson方法和数值去卷积方法，应用于使用简化的小肠吸收和转运模型模拟的剖面。小肠转运、溶出度和吸收速率常数在大致涵盖文献中观察到的数值范围内变化。针对每种参数组合分析IVIVC曲线图及其相应的相关系数，以确定反卷积方法在一系列速率限制条件下的适用性。对于高吸收制剂，在IVIVC过程中获得的相关系数在两种方法中都是相似的，并且随着溶出度的降低和转移率的增加而稳步下降。数值反褶积对IVIVC的适用性受吸收速率的影响不大，而当溶解速率超过吸收速率，吸收成为限速步骤时，Wagner-Nelson方法的适用性下降。预期输入和去卷积输入之间的差异是因为违反了去卷积的一个关键假设，即未知输入和单位脉冲在同一位置进入系统。
In vitro-in vivo correlations (IVIVCs) play an important role in formulation development and drug approval. At the heart of IVIVC is deconvolution, the method of deriving an in vivo “dissolution profile” for comparison with in vitro dissolution data. IVIVCs are generally believed to be possible for highly permeable and highly soluble compounds with release/dissolution as the rate-limiting step. In this manuscript, we apply the traditional deconvolution methods, Wagner-Nelson and numerical deconvolution, to profiles simulated using a simplified small intestine absorption and transit model. Small intestinal transit, dissolution, and absorption rate constants are varied across a range of values approximately covering those observed in the literature. IVIVC plots and their corresponding correlation coefficients are analyzed for each combination of parameters to determine the applicability of the deconvolution methods under a range of rate-limiting conditions. For highly absorbed formulations, the correlation coefficients obtained during IVIVC are comparable for both methods and steadily decline with decreasing dissolution rate and increasing transit rate. The applicability of numerical deconvolution to IVIVC is not greatly affected by absorption rate, whereas the applicability of Wagner-Nelson falls when dissolution rate overcomes absorption rate and absorption becomes the rate-limiting step. The discrepancy between the expected and deconvolved input arises from the violation of a key assumption of deconvolution that the unknown input and unit impulse enter the system in the same location.