Pediatric Development of Bosentan Facilitated by Modeling and Simulation.

BACKGROUND: Bosentan is approved for use in adult patients with pulmonary arterial hypertension. The primary aim of the pharmacokinetic modeling was the provision of a systematic guidance for study design and enhanced understanding of pharmacokinetics across the entire pediatric age range.

METHODS: A physiologically based pharmacokinetic model was developed for the pediatric population; starting from an adult model, the effects of body weight, age, and maturation of relevant metabolizing enzymes were incorporated to extrapolate the pharmacokinetics to children. A pediatric population pharmacokinetic model was developed to identify relevant covariates.

RESULTS: Based on model predictions, a dose of 0.5 mg/kg led to an exposure distinguishable from a dose of 2 mg/kg, and an additional blood sampling time point at 2 h (the predicted time of maximum concentration) allowed more precise estimation of bosentan exposure in children. The lower exposure observed in children compared with adults could be explained by maturation-related changes in clearance. Clinical data confirmed the model predictions.

CONCLUSIONS: Maturational changes in drug clearance and developmental changes in body weight were identified as key elements of bosentan pharmacokinetics in pediatric patients. Estimating bosentan exposure using physiologically based and population pharmacokinetic modeling and simulation supported dose selection in pediatric patients. Model-based exposure estimates helped in reducing the number of the youngest pediatric patients to be studied. Pharmacokinetic models can provide a systematic guidance for study design and enhanced understanding of pharmacokinetics across the entire pediatric age range.