Deconvolution Analysis by Non-linear Regression Using a Convolution-Based Model: Comparison of Nonparametric and Parametric Approaches

Abstract

The convolution-based modeling approach has been shown to be flexible and easy to implement for performing a deconvolution analysis and for assessing in vitro/in vivo correlation using non-linear regression and a pre-specified model describing the in vivo drug absorption. A generalization of this method has been developed using a nonparametric description of the in vivo drug absorption process in replacement of a model-based definition. A comparison of the parametric and nonparametric deconvolution and convolution analyses was conducted on the pharmacokinetic (PK) data observed in four published studies after the administration of an extended-release formulation of methylphenidate at the dose of 18 mg. All the analyses were conducted using a conventional non-linear regression software (NONMEM). The results of the deconvolution analysis indicated that the parametric and nonparametric approaches performed similarly. The parametric approach described the input function using a double Weibull equation (6 parameters) while the nonparametric approach described the input function using a piecewise approximation (12-13 parameters). The validation of the results of the deconvolution analysis was conducted by comparing observed and predicted PK concentrations by the convolution analysis. The performance of the parametric and nonparametric approaches for assessing deconvolution was evaluated using the Akaike and the Bayesian information criteria. These criteria indicated that, despite the similar results obtained with the two approaches, the nonparametric approach provided better results. In conclusion, these results indicated that the nonparametric approach should be considered as the preferred approach for conducting a deconvolution analysis.

Keywords: convolution; convolution-based model; deconvolution; nonparametric approach.