In Vivo Predictive Dissolution Testing of Montelukast Sodium Formulations Administered with Drinks and Soft Foods to Infants

Abstract

In vitro dissolution testing conditions that reflect and predict in vivo drug product performance are advantageous, especially for the development of paediatric medicines, as clinical testing in this population is hindered by ethical and technical considerations. The aim of this study was to develop an in vivo predictive dissolution test in order to investigate the impact of medicine co-administration with soft food and drinks on the dissolution performance of a poorly soluble compound. Relevant in vitro dissolution conditions simulating the in vivo gastrointestinal environment of infants were used to establish in vitro-in vivo relationships with corresponding in vivo data. Dissolution studies of montelukast formulations were conducted with mini-paddle apparatus on a two-stage approach: infant fasted-state simulated gastric fluid (Pi-FaSSGF; for 1 h) followed by either infant fasted-state or infant fed-state simulated intestinal fluid (FaSSIF-V2 or Pi-FeSSIF, respectively; for 3 h). The dosing scenarios tested reflected in vivo paediatric administration practices: (i.) direct administration of formulation; (ii.) formulation co-administered with vehicles (formula, milk or applesauce). Drug dissolution was significantly affected by co-administration of the formulation with vehicles compared with after direct administration of the formulation. Montelukast dissolution from the granules was significantly higher under fed-state simulated intestinal conditions in comparison with the fasted state and was predictive of the in vivo performance when the granules are co-administered with milk. This study supports the potential utility of the in vitro biorelevant dissolution approach proposed to predict in vivo formulation performance after co-administration with vehicles, in the paediatric population.

Performance Evaluation of Montelukast Pediatric Formulations: Part I—Age-Related In Vitro Conditions

“…Considering this, dissolution studies were performed under simulated fasted gastric to fasted intestinal conditions and simulated fasted gastric to fed intestinal conditions, and a higher % drug dissolved was observed in the fasted gastric to fed intestinal conditions testing, which is related to a higher drug solubility in fed state simulated media (14). The dissolution results are in accordance with a recent study where montelukast medicine co-administration practices were investigated in a two-stage dissolution approach using a mini-paddle apparatus (9). Similar to the results observed in this study, Martir et al showed that mixing medicines with food and drinks can affect drug product performance, and the in vitro dissolution of montelukast was higher under simulated fed intestinal conditions compared to simulated fasted state conditions (9).…”

“…The dissolution results are in accordance with a recent study where montelukast medicine co-administration practices were investigated in a two-stage dissolution approach using a mini-paddle apparatus (9). Similar to the results observed in this study, Martir et al showed that mixing medicines with food and drinks can affect drug product performance, and the in vitro dissolution of montelukast was higher under simulated fed intestinal conditions compared to simulated fasted state conditions (9).…”

“…The pediatric population undergoes continuous physiological and anatomical changes throughout childhood (4,5), making it highly unlikely for a single pediatric dissolution test to be able to represent newborns, infants, and children (6). The development of ageappropriate biorelevant dissolution methods is needed, and its relevance has been highlighted by several research groups in recent publications (4,5,(7)(8)(9)(10)(11).…”

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

“…Pediatric patients have additional ethical and technical constraints that affect the development of a suitable dosage form; these include the choice of the dosage form and its excipients, palatability, volume of administration, etc. (13). Further complications in the pediatric population arise as a result of the lack of formulations designed for the target pediatric population, which lead to drug manipulation practices (14)(15)(16), such as tablet splitting and crushing, and/or drug products being mixed with small amounts of food or drink vehicles to facilitate administration (14)(15)(16).…”

“…Currently, the main intended application of a pediatric PBPK model has been the proposal of initial dosing recommendation for pediatric clinical trials (22). Biorelevant in vitro dissolution studies, which take into account pediatric physiology, have started to appear in the literature (13,(23)(24)(25). The development of pediatric PBPK models focused on oral absorption coupled with in vitro dissolution may lead to discussions around pediatric biopharmaceutics and propose strategies to be used in pediatric drug development for the evaluation of age-related changes on drug product performance (6,8).…”