Implementation of Pharmacokinetic Bridging for Drug Combinations in Children
Massimo Cella (1,2), Meindert Danhof (1), Oscar Della Pasqua (1,2)
(1) Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, The Netherlands (2) Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, UK.
Objectives: The aim of this investigation is to show the relevance of adaptive protocols for dose selection in paediatric trials in early clinical development. The combination of antimalarial drugs atovaquone (ATV) and proguanil (PGN) was used as paradigm for the purposes of our evaluation.
Methods: Population pharmacokinetic models were developed for ATV and PGN using historical data in adults. Target exposure values for ATV and PGN were considered comparable in adults and children. Using simulations, a paediatric population (n= 40) was evaluated according to a range of scenarios in which clearance varied from 20% to 100% of the adult values, or allometrically correlated with body weight. The same initial dose was administered in all scenarios and the simulated concentration time profiles were then fitted using the SAEM method in NONMEM 7. Doses were adapted, if necessary, based on the individual AUC estimates.
Results: Systemic exposure expressed as AUCs (geometric means + percentiles) was significantly different across scenarios. Despite the evidence for higher exposures when the clearance was lower than in adults and high variability in drug disposition across the population, adaptation (titration) procedures were effective in ensuring target exposure was achieved in each individual patient.
Conclusions: An adaptive trial protocol is critical for accurate paediatric dose selection when evaluating drug combinations. It enables implementation of bridging concepts, taking into account the impact of covariates and other sources of variability on systemic exposure, which cannot be factored in a typical fixed design protocol. In contrast to current beliefs regarding the use of allometric methods only, flexible trial protocols are required to ensure target exposure is achieved for both active moieties.
