Modeling Complex Pharmacokinetics of Long‐Acting Injectable Products Using Convolution‐Based Models With Nonparametric Input Functions

Abstract

The interest in the development and the therapeutic use of long‐acting injectable (LAI) products for chronic or long‐term treatments has grown exponentially. The complexity and the multiphase drug release process represent serious issues for an effective modeling of the PK properties of LAI products. The objective of this article is to show how convolution‐based models with piecewise‐linear approximation of the nonlinear drug release function can provide an enhanced modeling tool for (1) characterizing the complex PK profiles of LAI formulations with completely different drug release properties, and (2) addressing key questions supporting the optimal development of LAI products by simulating the PK time course resulting from different dosing strategies. Convolution‐based modeling and simulation were implemented in NONMEM, and 3 case studies were presented to assess the performances of this new modeling approach using PK data of LAI products developed using different technologies and administered using different routes: microsphere technology and aqueous nanosuspension intramuscularly administered and biodegradable polymer subcutaneously administered. The performance of the convolution‐based modeling approach was compared with the performance of conventional parametric models using a reference data set on theophylline. The results of the comparison indicated that the nonparametric input function provided a more accurate description of the data either in terms of global measure of goodness of fit (ie, Akaike information criterion and Bayesian information criterion) or in terms of performance of the fitted model (ie, the percent prediction error on Cma x and AUC0‐t).