Tamara van Donge

Chapter 6 100 relatively low. 4,6 This variable success rate might be, for some part due to a lack data on pharmacokinetic (PK) and the exposure-response relationship of oral ibuprofen in preterm neonates with variable gestational and postnatal ages. 7 Ibuprofen is administered as a racemic mixture of R- and S-ibuprofen with the latter being responsible for its pharmacological effect. 8 Studies on enantiomer specific PK of intravenous ibuprofen in preterm neonates have shown that, despite a large variability in PK parameters, patient characteristics such as gestational age (GA) and postnatal age (PNA) are able to explain part of the between-subject variability of ibuprofen clearance. 9 In a study on exposure- response relationship, Hirt et al . (n = 67) linked exposure, defined as an area under the curve over the three days of treatment (AUC 0-72h ), to treatment success, with 91% success rate of PDA closure when total (R/S)-ibuprofen AUC 0-72h reached levels above 900 mg·h/L. 10 For optimal ibuprofen efficacy in each individual patient, the probability of reaching an adequate exposure needs to be increased. Individualizing the dose based on therapeutic drug monitoring (TDM) might be a possible approach. 11 However, the measurement of individual AUC 0-72h requires multiple sample collections, which is highly undesirable and burdensome in preterm neonates. 12 We are currently unaware of an optimal sampling strategy to estimate ibuprofen AUC 0-72h . The aims of this study are therefore a) to investigate the association between ibuprofen concentrations at various sampling time points and the AUC 0-72h , and b) to explore the feasibility of a novel TDM strategy where a single sample drawn on the first day of treatment will be sufficient to predict the target exposure. Methods Study design This prospective, single-center, open-label PK study was approved by the Hamilton Integrated Research Ethics Board (Hamilton, ON, CA, #4936-T). Written informed consent from a parent or legal guardian was obtained prior to study inclusion. Study population Eligible neonates were those with a gestational age ≤ 28 +6 weeks, admitted to the NICU at McMaster Children’s Hospital (MCH), and treated with oral ibuprofen for closure of a PDA. At the NICU of MCH, the decision for pharmacologic treatment of a PDA is made based on the echocardiographic or clinical findings that are deemed significant by the responsible medical team. Oral ibuprofen, which is being administered through a gastro-intestinal tube, is the first line treatment in neonates who i) are started on gastro-enteral feeding ii) do not have gastrointestinal morbidities and iii) do not have creatinine of ≥130 μmol/L or decreased urine output ≤1 mL/kg/h. Neonates with a PNA of ≤3 days received three daily