Application of modelling and simulation (M&S) methods within the context of a paediatric-use marketing authorisation (PUMA) application
Esther Encinas (1), Valvanera Vozmediano (1), Monica Rodriguez (1), Flavia de Toni (1), Nerea Leal (1), Helen Shaw (2)
(1) Drug Modeling & Consulting, Dynakin SL, Derio, Bizkaia, Spain, (2) Proveca Ltd., Daresbury, Cheshire, United Kingdom
Objectives: To develop a pharmacokinetic (PK) model for a dedicated new oral paediatric formulation (active substance so far used off-label), based on a comparative bioavailability (BA) study performed in adults against a comparator product registered outside Europe (reference), and to apply it for bridging to the public domain clinical efficacy and safety data available for the later in children, in support of a PUMA application.
Methods: PK data were obtained from a single dose, two-way crossover comparative BA study in 65 fasted adult volunteers. Plasma levels for each product were separately fitted to a compartmental PK model using non-linear mixed-effects modelling implemented in NONMEM [1] (FOCE method). Final PK models were subsequently scaled to children aged 3 years and above by using simple allometric expressions on clearance and volume of distribution [2]. Assuming the same variability as observed in adults, paediatric models were then applied, via simulation, to guide the selection of the dose titration regimen as well as to give response to a list of questions raised by the European Medicines Agency (EMA).
Results: A one-compartment model with sequential two first-order absorption rates and additive residual error was found to best describe the drug PK for both oral formulations in adults. None of the studied covariates (e.g., age, body weight, sex and race) was statistically significant. PK modelling revealed that lower BA observed for the new formulation could be attributed to minor dissimilarities between products at the absorption level, whereas systemic processes (i.e., distribution and elimination) were mostly formulation-independent. Simulation of steady-state drug plasma levels in paediatrics allowed to adjust the dose titration schedule for the new formulation by targeting a comparable exposure to that achieved with the foreign comparator. Model-based simulations also served as a guiding tool to recommend a 30% reduction in posology in renal impairment paediatric patients [3], to demonstrate similar food effect between formulations and to ensure the cardiovascular safety of the proposed regimen.
Conclusions: Application of M&S methods within the context of a PUMA application for a dedicated new paediatric formulation allowed to satisfactorily establish a link to the public domain knowledge on the drug efficacy and safety profile while avoiding unnecessary studies in the paediatric population.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.
[2] Anderson BJ, Holford NHG. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet. 2009;24(1):25–36.
[3] Daschner M. Drug dosage in children with reduced renal function. Pediatr Nephrol. 2005;20(12):1675–1686.