Empagliflozin in paediatric heart failure: model-based optimisation of a pharmacokinetic bridging study
Abstract
Aims: Current therapy for paediatric heart failure is still unsatisfactory, and trials in this population have often failed. Here we apply a model-based approach to optimise the study design and increase the probability of success of a prospective trial aimed at establishing the dose rationale for empagliflozin in children with heart failure. The proposed prospective protocol is based on the assumption that the cardioprotective mechanisms and efficacy of SGLT-2 inhibitors in the paediatric population can be extrapolated from adults. Methods: A nonlinear mixed effects modelling approach incorporating prior information from pharmacokinetics (PK) in adults was used to extrapolate empagliflozin disposition parameters to children with ≥15 kg body weight. Protocol elements of interest were sampling schedule, dose, and sample size. These features were explored using an optimization algorithm ($DESIGN) and a simulation re-estimation procedure (SSE) in a large virtual paediatric cohort, overcoming some of the difficulties associated with low parameter precision in small populations. Results: A two-compartment pharmacokinetic model with sequential zero- and first-order absorption, absorption lag time and first-order elimination was identified. Clearance and distribution parameters were assumed to vary allometrically with body weight. We defined the lowest weight of 15 kg as inclusion criterion for the prospective trial, achieving, with the lowest commercially available tablet of 10…
How strong is the evidence?
Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 12 participants or records.
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