(T1130-09-50) Biopharmaceutical Tools for De-risking Paediatric Formulation Development

Purpose: Drug formulation development for paediatrics can be quite a complicated process due to their changing anatomy and physiology which can lead to large variability between individuals. Clinical trials in paediatric populations are often limited due to ethical concerns and therefore trials for paediatric formulations are usually undertaken in adult populations. Bridging studies using in vitro biorelevant tests can minimise risks in the paediatric formulation development process. As during a clinical study, an adult would be recommended to consume 240 mL of water with the formulation, the impact of water-intake volume during a relative bioavailability study of a paediatric formulation should be considered. In this study the risk of variable water-intake volume for a dispersible artesunate (AS) and piperaquine (PQP) combination tablet was assessed with the appropriate in vitro biopharmaceutical tools and validated with clinical data. Furthermore, the bridging from an AS-PQP film-coated tablet to the paediatric dispersible tablet was successfully predicted using in vitro biorelevant tests.

Methods: To evaluate the effect of co-administered water volumes, dissolution of the dispersible AS-PQP tablet was conducted in a single-stage dissolution study using the USP II apparatus in 250 mL of adult fasted-state gastric media (FaSSGF). The tablet was either administered directly or with an additional water volume of 50 mL (low) or 240 mL (high). All experiments were performed at 37°C for 240 min at 50 rpm. Samples were collected during the dissolution process and drug quantities analysed using HPLC. To assess the bridging from the film-coated tablet to the AS-PQP dispersible tablet a single- and a two-stage dissolution set up were used. The single-stage study was conducted in the USP II apparatus under simulated fasted gastric conditions (FaSSGF). The two-stage dissolution study was conducted on a USP IV apparatus with sequential media change from fasted gastric (FaSSGF – 30 min, 12 mL/min) to fasted intestinal (FaSSIF.V2 – 240 min, 4 mL/min) conditions. Samples were collected at specific time intervals and drug quantities analysed using HPLC.

Results: The results from the study showed that the dissolution performance of the dispersible tablet was independent of the co-administered water volume. The three investigative compounds; artesunate, dihydroartemisinin and piperaquine all showed similar in vitro AUC_{0-240 min} values across the tested water-intake volumes. The AS-PQP dispersible tablet was also not impacted in vivo when a lower co-administered water volume was given compared to the standard 240 mL, revealing the predictive power of the in vitro tests and the development of a successful in vitro-in vivo relationship (IVIVR) (Figure 1). The AS-PQP dispersible tablet had a faster initial dissolution rate compared to the AS-PQP film-coated tablet, but a similar in vitro performance overall. The similar in vitro AUC_{0-240 min} between the two formulations reflected the similar observed bioavailability results in the clinical studies (Figure 2).

Conclusion: In vitro biopharmaceutics tests were conducted on paediatric AS-PQP dispersible tablets to give confidence in the bridging process by limiting potential risks. This study assessed whether the volume of co-administered water affects the dispersible formulation behaviour and its equivalence to the AS-PQP film-coated tablet. Results showed that the water-intake volume does not affect the performance of the dispersible formulation minimising the risk of not achieving target therapeutic outcomes as paediatric patients could have a lower water-intake volume compared to adults. The dispersible formulation also was equivalent to the film-coated tablet. All results in this study were reflective of the clinical data associated with the formulations revealing the predictive power of the in vitro tests.

Acknowledgements: This publication is based on research funded in part by the Bill & Melinda Gates Foundation. The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the Bill & Melinda Gates Foundation.

Figure 1. % AUC50mL/ AUC240mL observed in vitro (USPII apparatus) and in vivo for (a) DHA and (b) PQP (dotted lines reflect the bioequivalence criteria 80-125%).

Figure 2. % AUCdispersible/ AUCfilm-coated observed in vitro (USPIV apparatus) and in vivo for (a) DHA and (b) PQP (dotted lines reflect the bioequivalence criteria 80-125%).