Pharmacokinetic Simulations Involving Convolution Approaches

Abstract

This thesis is a part of a research project on pharmacokinetic modeling of enteric coated microparticulate formulations of Metoprolol tartrate. First part of this study dealt with pharmaceutical aspects i.e. formulation development, while second part of study dealt with mathematical modeling of pharmacokinetics. Firstly, this study was aimed to develop in vitro in vivo correlation (IVIVC) level A, B and C for encapsulated Metoprolol tartrate (T1, T2 and T3 having Metoprolol tartrate/polymer ratio of 1:1, 1:1.5 and 1:2 by weight/weight). The in vitro data was correlated with in vivo data. For IVIVC level A, drug absorption data was calculated using Wagner-Nelson method. In addition, convolution approach was used to approximate plasma drug levels from in vitro dissolution data. The coefficient of determination (R2) for level A was 0.720, 0.905, 0.928 and 0.878 for Mepressor®, T, T2 and T3 formulations, respectively with acceptable percent error (<15%). The value of (R2) for level B and C was 0.231 and 0.714, respectively. It is also concluded that IVIVC level A is a proficient mathematical model for biowaiver studies involving study parameters as those implemented for T1S (T1 formulation tested for dissolution in the presence of sodium lauryl sulphate) revealing that IVIVC level A is dosage form specific, rather than to be drug specific. Secondly, the aimed of this study was to assess and apply the in vitro to in vivo profiling (IVIVP), a new biowaiver approach, in designing a product with specific release pattern. The IVIVC was established by plotting the observed and predicted plasma drug concentrations. For IVIVC, convolution approach was employed to estimate plasma drug concentrations from in vitro dissolution profiles. The IVIVC for T1S exhibited a good correlation coefficient (R2 = 0.963) followed by the T2 (R2 = 0.682), T3 (R2 = 0.665), T1 (R2 = 0.616), and Mepressor® (R2 = 0.345). Establishing an IVIVP, based on IX the convolution approach, can be more useful and practicable in the biowaiver studies, rather than present complicated practice of IVIVC estimated via deconvolution approach. This study also elaborates that there is good correlation between the IVIV profiles of the developed Metoprolol tartrate formulations, particularly for T1S.