Population pharmacokinetics of methylprednisolone in neonates and paediatric patients undergoing cardiac surgery with cardiopulmonary bypass

<title>Abstract</title> <bold>Purpose</bold> Methylprednisolone is commonly used during paediatric cardiac surgery with cardiopulmonary bypass to attenuate the systemic inflammatory response. However, developmental differences in drug disposition and procedural factors such as circuit priming introduce significant variability in drug exposure, and optimal dosing remains uncertain. our objective is to develop a population pharmacokinetic model for methylprednisolone in neonates and young paediatric patients undergoing open-heart surgery and to evaluate dosing strategies using model-based simulations. <bold>Methods</bold> Data were pooled from four prospective clinical studies including 93 patients aged 1 to 574 days undergoing cardiac surgery with cardiopulmonary bypass. Methylprednisolone was administered as an intravenous bolus after anaesthesia induction or via the cardiopulmonary bypass circuit at doses of 5 or 30 mg/kg. Plasma concentrations were measured at predefined perioperative timepoints. A nonlinear mixed-effects model was developed using NONMEM. Covariate effects of weight, age, cardiopulmonary bypass duration, and dosing route were explored. Model evaluation included diagnostic plots, bootstrapping, and visual predictive checks. Simulations were used to explore alternative dosing strategies across age groups. <bold>Results</bold> A two-compartment model with first-order elimination adequately described the data. Clearance was influenced by allometrically scaled body weight. Neonates exhibited lower clearance and longer half-life than older children. Simulations showed that higher doses may be unnecessary in neonates and risk excessive exposure. <bold>Conclusion</bold> This model provides a framework for individualized dosing of methylprednisolone in paediatric cardiac surgery. Tailored dosing strategies based on age and weight may improve safety and therapeutic consistency, particularly in neonates. <bold>Trial registration number and date</bold> : EudraCT 2008-007413-76 2008-12-23