Multiple-dose pharmacokinetics of rectally administered acetaminophen in term infants

Objective
To investigate pharmacokinetics and pharmacodynamics of rectally administered acetaminophen (INN, paracetamol) in term neonates directly after birth.

Methods
In this prospective clinical trial, term neonates wtih painful conditions or who were undergoing painful procedures received multiple-dose acetaminophen. Serum concentrations were determined serially with an HPLC method, and pharmacokinetic analysis was performed. Pain assessment was performed by means of a validated pain score.

Results
Ten consecutive term neonates received four rectal doses of acetaminophen, 20 mg/kg body weight, every 6 hours. Mean peak serum concentrations (±SD) during multiple-dose administration were 10.79 ± 6.39 mg/L, 15.34 ± 5.21 mg/L, and 6.24 ± 3.64 mg/L for the entire group, boys, and girls, respectively. There was a significant difference between the boys and the girls (P = .01). No serum concentrations associated with toxicity (>120 mg/L) were found. Median time to peak serum concentration was 1.5 hours after the first dose and 15 hours for multiple doses. Mean (±SD) half-life was 2.7 ± 1.4 hours in eight patients. There was no correlation between dose and serum concentration or between pain score and serum concentration. There was a significant inverse relationship between the preceding pain score and peak serum concentrations.

Conclusions
In term neonates, multiple rectal doses of acetaminophen, 20 mg/kg body weight, led to widely varying serum concentrations but did not result in therapeutic concentrations in all infants. Boys had higher peak concentrations. Because accumulation was not found, a dose of 30 mg/kg followed by doses of 20 mg/kg at 6- to 8-hour administration intervals are appropriate to reach therapeutic concentrations. A concentration–effect relationship could not be determined.