Assessing Whether Controlled Release Products with Differing in Vitro Dissolution Rates Have the Same in Vivo-in Vitro Relationship
In order to demonstrate a complete in vivo-in vitro correlation (IVIVC) for a controlled release (CR) formulation, it is necessary that the relationship between in vivo percent absorbed and in vitro percent dissolved be the same whether the dissolution rate is as targeted or whether the dissolution rate is faster or slower than intended for the marketed product. This is essential if the IVIVC will be used in the future for a decision on the acceptability of a change in the formulation. Suppose that a four period cross-over study is performed, with each subject receiving the to-be-marketed CR product, a product with a faster in vitro dissolution rate, a product with a slower dissolution rate, and an intravenous dose (or perhaps an oral dose of an immediate release formulation). Using an appropriate deconvolution method, for each subject and each CR product the percent absorbed is estimated for each time post dose for which the in vitro percent dissolved is measured. We present a method for the assessment of whether the relationship between in vivo percent absorbed and in vitro percent dissolved is the same for the three CR products
Statistical analysis of the data should be done taking into account the dependence of the data points from the same subject. (Each subject contributes an estimate of percent absorbed for several time points for each CR product.) The use of mixed effect models is discussed. A data point consists of the in vitro percent dissolved at a given time for one of the CR products and the measure of percent absorbed for a given subject at the same time post dose for this CR product. The subjects of the study are viewed as a sample from a large population. The parameters of greatest interest define the relationship (e.g. a linear relationship) between the population central value for percent absorbed and the in vitro percent dissolved. Analyses are performed to address the question of whether the values of the parameters that define the relationship between percent absorbed central value and in vitro percent dissolved are the same for the three CR products (i.e. to address the question of whether the IVIVC is the same for the three CR products).
KeywordsDissolution Rate Period Effect Mixed Effect Model Multivariate Normal Distribution NONMEM Package
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