• G M Palmer, M Atkins, B J Anderson, K R Smith, T J Culnane, C M McNally, E J Perkins, G A Chalkiadis, and R W Hunt.
• Department of Paediatric Anaesthesia and Pain Management, Royal Children's Hospital, Flemington Road, Parkville, Melbourne, VIC 3052, Australia. greta.palmer@rch.org.au
• Br J Anaesth. 2008 Oct 1;101(4):523-30.

BackgroundPharmacokinetics of an i.v. prodrug of acetaminophen (propacetamol) in neonates after repeat dosing are reported, with scant data for i.v. acetaminophen formulation.MethodsNeonates from an intensive care unit received 6-hourly prn i.v. acetaminophen dosed according to postmenstrual age (PMA): 28-32 weeks, 10 mg kg(-1); 32-36 weeks, 12.5 mg kg(-1); and > or =36 weeks, 15 mg kg(-1). A maximum of five blood samples for assay and liver function tests (LFTs) were collected. A one-compartment linear disposition model (zero-order input; first-order elimination) was used to describe time-concentration profiles using population modelling (NONMEM).ResultsFifty neonates, median (range) PMA 38.6 (32-45) weeks, mean (SD) weight 2.9 (0.7) kg, received a mean of 15 doses over a median 4 days with 189 serum acetaminophen and 231 LFT measurements. Standardized population parameter estimates for a term neonate were clearance (CL) 5.24 (CV 30.5%) litre h(-1) 70 kg(-1) and volume of distribution (V) 76 (29.6%) litre 70 kg(-1). CL increased with PMA from 4.4 litre h(-1) 70 kg(-1) at 34 weeks to 6.3 litre h(-1) 70 kg(-1) at 46 weeks. The presence of unconjugated hyperbilirubinaemia was associated with reduced CL: 150 micromol litre(-1) associated with 40% CL reduction. Acetaminophen concentrations between 10 and 23 mg litre(-1) at steady state are predicted after 15 mg kg(-1) 6-hourly for a neonate of PMA 40 weeks. Hepatic enzyme analysis of daily samples changed significantly for one patient whose alanine aminotransferase concentration tripled.ConclusionsThe parameter estimates are similar to those described for propacetamol. There was no evidence of hepatotoxicity. Unconjugated hyperbilirubinaemia impacts upon CL, dictating dose reduction.

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