A Semi-mechanistic Modeling Strategy to Link In Vitro and In Vivo Drug Release for Modified Release Formulations

ABSTRACT Purpose To develop a semi-mechanistic model linking in vitro to in vivo drug release. Methods A nonlinear mixed-effects model describing the in vitro drug release for 6 hydrophilic matrix based modified release formulations across different experimental conditions (pH, rotation speed and ionic strength) was developed. It was applied to in vivo observations of drug release and tablet gastro intestinal (GI) position assessed with magnetic marker monitoring (MMM). By combining the MMM observations with literature information on pH and ionic strength along the GI tract, the mechanical stress in different parts of the GI tract could be estimated in units equivalent to rotation speed in the in vitro USP 2 apparatus. Results The mechanical stress in the upper and lower stomach was estimated to 94 and 134 rpm, respectively. For the small intestine and colon the estimates of mechanical stress was 93 and 38 rpm. Predictions of in vivo drug release including between subject/tablet variability was made for other newly developed formulations based on the drug release model and a model describing tablet GI transit. Conclusion The paper outlines a modeling approach for predicting in vivo behavior from standard in vitro experiments and support formulation development and quality control.