LEVEL-A IN-VITRO IN-VITRO CORRELATION - NONLINEAR MODELS AND STATISTICAL METHODOLOGY

Some new nonlinear models for the relationship between the fraction of drug dose dissolved (absorbed) in vivo and that dissolved in vitro ar e described. The models are empirical in nature and are generalization s of the linear model that, at present, is the most commonly used mode l. The modeling approach is based on considering the time at which a d rug molecule goes into solution (in vitro or in vivo) to be a random v ariable and relating the distribution functions using proportional odd s, proportional hazards, and proportional reversed hazards models. The models are further extended by allowing the parameter that relates in vivo and in vitro to be a function of time. A statistical model for t he data is developed and used as the basis for a statistical methodolo gy for fitting these models. The methods are shown to be generalized l inear mixed effects model (GLMM) methods. The models are fitted to som e data sets, and the results demonstrate that these models have potent ial.