Convolution-based approach for modeling the paliperidone extended release and Long-Acting Injectable (LAI) PK of once-, and three-monthly products administration and for optimizing the development of new LAI products

The aim of this paper was to develop a convolution-based modeling approach for describing the paliperidone PK resulting from the administration of extended-release once-a-day oral dose, and once- and three monthly long-acting injectable products and to compare the performances of this approach to the traditional modeling strategy. The results of the analyses indicated that the traditional and convolution-based models showed comparable performances in the characterization of the paliperidone PK. However, the convolution-based approach showed several appealing features that justify the choice of this modeling as a preferred tool for modeling Long Acting Injectable (LAI) products and for deploying an effective model-informed drug development process. In particular, the convolution-based modeling can (a) facilitate the development of in vitro/in vivo correlation, (b) be used to identify formulations with optimal in vivo release properties, and (c) be used for optimizing the clinical benefit of a treatment by supporting the implementation of integrated models connecting in vitro and in vivo drug release, in vivo drug release to PK, and PK to PD and biomarker endpoints. A case study was presented to illustrate the benefits and the flexibility of the convolution-based modeling outcomes. The model was used to evaluate the in vivo drug release properties associated with a hypothetical once-a-year administration of a LAI product with the assumption that the expected paliperidone exposure during a 3-year treatment overlays the exposure expected after repeated administrations of a 3-month LAI product.