Application of the Simcyp Population‐based PBPK Simulator to the Modelling of MR Formulations

Use of In Vitro Dynamic Colon Model (DCM) to Inform a Physiologically Based Biopharmaceutic Model (PBBM) to Predict the In Vivo Performance of a Modified-Release Formulation of Theophylline

“…There are two ways for the ADAM model to handle in vitro dissolution/release profiles of MR formulations, either as a dissolution profile or as a release profile [ 15 ]. In the first case (dissolution profile), the model converts the mass of the API in the MR formulation to dissolved drug according to dissolution rate over time.…”

“…This is because a mechanistic understanding of the complex interplay of polymers, drugs, gastrointestinal (GI) components (e.g., buffer species and bile salts) and hydrodynamics (e.g., motility and shear forces) as well as food effects (e.g., viscosity, fat, protein and fibre) is required, which is not an easy task. Thus, the current approaches to simulating the in vivo dissolution of drug particles from MR formulations are (a) to use the in vitro compendial dissolution profile as a release profile and allow mechanistic models (e.g., Advanced Dissolution Absorption Metabolism (ADAM) in Simcyp ® or Advanced Compartmental Absorption and Transit (ACAT TM ) in Gastroplus ® ) to handle the dissolution of the released drug particles [ 15 , 16 ]; (b) to directly import the dissolution profile into the PBBM (although this is not recommended as it removes inter-subject variability from the simulations); and (c) to fit the in vitro dissolution profile, mainly derived from USP apparatuses, using a Weibull function [ 17 , 18 ]. Thus, the most important input to the PBBMs for MR formulations is still the in vitro dissolution profile.…”