Tamara van Donge

Abstract Objective : Exploration of a novel therapeutic drugmonitoring (TDM) strategy to personalize use of ibuprofen for closure of patent ductus arteriosus (PDA) in preterm neonates. Design : Prospective, single-center, open-label, pharmacokinetics study in preterm neonates. Setting : Neonatal Intensive Care Unit at McMaster Children’s Hospital. Patients : Neonates with a gestational age ≤ 28 +6 weeks treated with oral ibuprofen for closure of a PDA. Methods : Population pharmacokinetic parameters, concentration-time profiles and exposure metrics were obtained using pharmacometric modeling and simulation. Main outcome measure : Association between ibuprofen plasma concentrations measured at various sampling time points on the first day of treatment and attainment of the target exposure over the first three days of treatment (AUC 0-72h >900 mg·h/L). Results : Twenty-three preterm neonates (median birth weight 780 g and gestational age 25.9 weeks), were included, yielding 155 plasma ibuprofen plasma samples. Starting from 8 hours’ post-dose on the first day, a strong correlation between ibuprofen concentrations and AUC 0-72h was observed. At 8 hours after the first dose, an ibuprofen concentration >20.5 mg/L was associated with a 90% probability of reaching the target exposure. Conclusion : We designed a novel and practical TDM strategy and have shown that the chance of reaching the target exposure (AUC 0-72h >900 mg·h/L) can be predicted with a single sample collection on the first day of treatment. This newly acquired knowledge can be leveraged to personalize ibuprofen dosing regimens and improve the efficacy of ibuprofen use for pharmacological closure of a PDA. Keywords : preterm neonates, ibuprofen, patent ductus arteriosus (PDA), minimum concentration (C min ), therapeutic drug monitoring (TDM), pharmacometric modeling and simulation