Palmer GM, Atkins M, Anderson BJ, Smith KR, Culnane TJ, McNally CM, Perkins EJ, Chalkiadis GA, Hunt RW
I.V. acetaminophen pharmacokinetics in neonates after multiple doses. [JOURNAL ARTICLE]
Br J Anaesth 2008 Jul 15.
BACKGROUND: /st> Pharmacokinetics of an i.v. prodrug of acetaminophen (propacetamol) in neonates after repeat dosing are reported, with scant data for i.v. acetaminophen formulation.
METHODS: /st> Neonates 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 >/=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).
RESULTS: /st> Fifty 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.
CONCLUSIONS: /st> The 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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