From lab-to-clinic with model informed formulation development: a case study of hydroxyzine SR tablets

Model Informed Formulation Development (MIFD) uses physiologically based pharmacokinetic (PBPK) modelling and other <i>in silico</i> tools to facilitate new product development. These tools help set target profiles, predict <i>in vivo</i> formulation performance, guide iterative development, define dissolution parameters, and convince the regulatory agencies about a drug’s safety and efficacy.This study involves development of a sustained release formulation for Hydroxyzine, an anti-histamine with sedation as a significant side effect. The aim was to design a formulation that releases the drug slowly, reducing the peak plasma concentration without losing on the effectiveness. A preliminary absorption model was developed using immediate release formulation data, and various hypothetical dissolution profiles were evaluated in this model. The new drug product, manufactured using Matrixeal^TM technology, underwent preliminary bioequivalence (BE) studies in healthy volunteers. These results were used to refine the model and further modify the formulation, whose performance was predicted <i>via</i> virtual BE studies. Confirmatory BE studies with 70 volunteers under fasting state validated the new formulation. The model also established clinically relevant dissolution specifications and assessed the food effect on the drug product.This work showcases the application of PBPK modelling in developing new modified release drug product of Hydroxyzine. Model Informed Formulation Development (MIFD) uses physiologically based pharmacokinetic (PBPK) modelling and other <i>in silico</i> tools to facilitate new product development. These tools help set target profiles, predict <i>in vivo</i> formulation performance, guide iterative development, define dissolution parameters, and convince the regulatory agencies about a drug’s safety and efficacy. This study involves development of a sustained release formulation for Hydroxyzine, an anti-histamine with sedation as a significant side effect. The aim was to design a formulation that releases the drug slowly, reducing the peak plasma concentration without losing on the effectiveness. A preliminary absorption model was developed using immediate release formulation data, and various hypothetical dissolution profiles were evaluated in this model. The new drug product, manufactured using Matrixeal^TM technology, underwent preliminary bioequivalence (BE) studies in healthy volunteers. These results were used to refine the model and further modify the formulation, whose performance was predicted <i>via</i> virtual BE studies. Confirmatory BE studies with 70 volunteers under fasting state validated the new formulation. The model also established clinically relevant dissolution specifications and assessed the food effect on the drug product. This work showcases the application of PBPK modelling in developing new modified release drug product of Hydroxyzine.