Scaling of fixed-dose combinations in children
Massimo Cella(1), Frank Kloprogge(1), Meindert Danhof(1) and Oscar Della Pasqua(1,2)
(1)Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands, (2)Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Greenford, UK
Objectives: Drug combinations with fixed dose ratio are standard therapy for various infectious diseases. In these circumstances, dose adjustment in children has been dealt with in the same way as single agent therapy, under the assumption that a comparable risk : benefit ratio is maintained across populations. The objective of this investigation was to evaluate the implications of the scaling of dosing regimens by body weight using the combination of antimalarial drugs atovaquone (ATV) and proguanil (PGN) as example. This combination is prescribed in the ratio (2.5:1) in adults and children. We hypothesise that different dose ratios may be required for some drugs to ensure that exposure to either moiety is equivalent to that observed in adults.
Methods: Atovaquone and proguanil plasma concentrations of 783 subjects (301 adults and 482 children) were obtained from 9 different clinical studies. Both drugs were administered orally at different dose levels. A population pharmacokinetic model was developed using NONMEM 6.2. A one compartment model with 1st order absorption and elimination best described the pharmacokinetic profiles of ATV and PGN. The parameter estimates from the PK model were then used to simulate drug exposure in children following different dose levels. Simulation datasets included patients across a wide range of weights (5, 10, 15, 25, 35, 70 kg).
Results & Conclusions: Preliminary results show that the assumption a priori of a fixed ratio between two active compounds when scaling the dose from adults to children may lead to inappropriate exposures in the paediatric population. Adjustment of the dose ratio according to the distribution of covariates affecting the pharmacokinetics of either moiety is critical to achieving effective and safe exposure across a wide weight /age range. A model-based approach seems critical to prevent failure in paediatric trials with fixed dose combinations.
