Performance Evaluation of Montelukast Pediatric Formulations: Part II — a PBPK Modelling Approach

Abstract

This study aimed to build a physiologically based pharmacokinetic (PBPK) model coupled with age-appropriate in vitro dissolution data to describe drug performance in adults and pediatric patients. Montelukast sodium was chosen as a model drug. Two case studies were investigated: case study 1 focused on the description of formulation performance from adults to children; case study 2 focused on the description of the impact of medicine co-administration with vehicles on drug exposure in infants. The PBPK model for adults and pediatric patients was developed in Simcyp® v18.2 informed by age-appropriate in vitro dissolution results obtained in a previous study. Oral administration of montelukast was simulated with the ADAM™ model. For case study 1, the developed PBPK model accurately described montelukast exposure in adults and children populations after the administration of montelukast chewable tablets. Two-stage dissolution testing in simulated fasted gastric to intestinal conditions resulted in the best description of in vivo drug performance in adults and children. For case study 2, a good description of in vivo drug performance in infants after medicine co-administration with vehicles was achieved by incorporating in vitro drug dissolution (under simulated fasted gastric to fed intestinal conditions) into a fed state PBPK model with consideration of the in vivo dosing conditions (mixing of formulation with applesauce or formula). The case studies presented demonstrate how a PBPK absorption modelling strategy can facilitate the description of drug performance in the pediatric population to support decision-making and biopharmaceutics understanding during pediatric drug development. Graphical abstract

Montelukast: results and prospects for applications in pediatric practice

“…Как указано выше, CysLTRs опосредуют действие лейкотриенов, участвующих в патогенезе различных аллергических заболеваний дыхательной системы, включая БА, астму, вызванную физической нагрузкой, приемом аспирина, и АР. Лейкотриены приводят к сужению дыхательных путей, сокращению гладкой мускулатуры и таксису нейтрофилов и эозинофилов в очаг воспаления [23].…”