Paracetamol and Patent Ductus Arteriosus closure: Pharmacokinetic-Pharmacodynamic study

Paracetamol administration for PDA closure is a standard of care for all preterm neonates at Monash Newborn. Paracetamol will be used for PDA closure after confirming haemodynamically significant PDA on echocardiography Dose: First course- 15 mg/kg every 6 h for three days, administered either intravenously or orally for infants tolerating trophic feeds (>10ml/kg/day). The second ECHO assessment is done within 24 h of the completion of first course. A second course of paracetamol for three days (15mg/kg every 6 h) is given if there is ductal patency The following is the baseline blood testing as standard of care before paracetamol therapy is commenced at Monash Newborn- Baseline creatinine, liver function test and platelet count will be checked before the commencement of paracetamol therapy. The therapy will be withheld when alanine transaminase and gamma glutamyl transferase levels >100 U/l and/or >200 U/l, respectively, or serum creatinine >100 mmol/l or platelet count <100 X109/l; and will be restarted if levels normalized 24–72 h later. Repeat serum creatinine, liver function test and platelet count will be checked at the same time of checking paracetamol trough concentration before 12th dose Additional blood testing as part of this study- Paracetamol concentrations will be collected either as ‘peak’ or ‘trough’, whereby ‘peak’ is 30 minutes after the end of the 30-minute IV infusion, and ‘trough’ is immediately prior to the next 6 hourly dose. On the first day of dosing, 2 samples will be taken after the first dose, both ‘peak’ and ‘trough’. Subsequently, a daily sample will be taken, alternating between ‘trough’ and ‘peak’ concentration. Following completion of 3-day course, a daily ‘washout’ sample will be taken for 2 subsequent days Sampling schedule: • Day 1: o Peak 30m after end of 1st dose o Trough just before 2nd dose on Day 1 • Day 2 o Peak 30m after end of 5th dose • Day 3 o Trough just before the 12th dose • Day 4 (washout) o Random sample • Day 5 (washout) o Random sample If participant undergoes a second course of paracetamol treatment, the sampling procedure will start over as above. • Day 1: o Peak 30m after end of 1st dose o Trough just before 2nd dose on Day 1 • Day 2 o Peak 30m after end of 5th dose • Day 3 o Trough just before the 12th dose • Day 4 (Second Course) o Peak 30m after end of 1st dose (cumulative 13th dose) o Trough just before 2nd dose (cumulative 14th dose) • Day 5 o Peak 30m after end of 5th dose (cumulative 17th dose) • Day 6 o Trough just before the 12th dose (cumulative 24th dose) • Day 7 (washout) o Random sample • Day 8 (washout) o Random sample Additional ‘scavenged’ samples will be taken in an opportunistic manner whenever blood is taken as part of clinical care (with a small aliquot used for paracetamol concentration along with documentation of time taken). • Every day 1-6: o All possible scavenged samples will be sent for analysis (additional volume from clinical draws) will be sent for analysis. Throughout the study, paracetamol concentrations will be assayed in real time, with identification of outliers in exposure allowing for empiric (PK uninformed) dose adjustment. Total volume: A minimum sample volume for a stand-alone test is a blood volume 120 µL providing 50µL serum/plasma (assay volume 10 µL plus 40µL dead space). If testing is ‘opportunistic’ at the time of other clinical tests additional serum/plasma volume is 10µL.