In Vitro Scaling of Nebulised Doses of ETD001 for Clinical Trials in Paediatric Subjects with Cystic Fibrosis

Eddie J French¹, Samantha Heath³, Joanne Charlwood², Paul Russell²
Kathy Woodward² Niyati Prasad² & Thomas Moody³

¹ TEKH Consulting Limited, Queen Street Deal CT13 6EY UK

²Enterprise Therapeutics Ltd., Sussex Innovation Centre, Falmer, Brighton, BN1 9SB, UK

³Intertek Melbourn, Saxon Way, Melbourn, Hertfordshire, SG8 6DN, United Kingdom

Summary

 Early clinical trials are usually undertaken solely in an adult population. When designing clinical trials to include paediatric patients, the prospective clinical dose may need to be suitably adjusted to reduce the possibility of under or overdosing.  Scaling of prospective inhaled clinical doses from an adult dose, based solely on relative body weight or body surface area does not account for the change in delivery efficiency of the formulation to paediatric populations compared to adults.

ETD001 is a novel inhaled ENaC (Epithelial sodium Channel) blocker being developed by Enterprise Therapeutics Ltd. to enhance mucociliary clearance in people with cystic fibrosis. ETD001 is currently in phase 2 clinical trials and clinical studies are being designed for the paediatric population in discussion and agreement with the regulators in Paediatric Investigational Plan (PIP). An in-vitro assessment of relative dosing efficiency was undertaken for ETD001 solution delivered by a nebuliser.

The aerosol particle size distribution (aPSD) via Next Generation Impactor (NGI) using both USP and Alberta idealised throats and the delivered dose, using various paediatric breathing profiles with face masks on anatomical face models, were assessed using pharmacopeial methods. The testing demonstrated for infants there is a 4 fold reduction and for babies a 6.5 fold reduction in dose reaching the lungs from the same nominal dose.

In vitro studies using anatomically representative models and appropriate breathing cycles can significantly enhance the ability to scale doses for paediatric clinical studies with inhaled therapies by predicting the relative delivery efficiency from a nebuliser. These factors need to be taken into consideration when calculating clinical doses for paediatric subjects as scaling doses based solely on body weight could lead to significant underdosing.

 Key Message

The use of anatomically relevant models and breathing profiles in the in-vitro scaling of inhaled clinical doses from an adult dose to those for paediatrics, allows for the relative reduction in delivery efficiency of the formulation to be taken into account, especially if a facemask is used for administration.