Acetaminophen developmental pharmacokinetics in premature neonates and infants - A pooled population analysis

Background: The aim of this study was to describe acetaminophen developmental pharmacokinetics in premature neonates through infancy to suggest age-appropriate dosing regimens. Methods: A population pharmacokinetic analysis of acetaminophen time-concentration profiles in 283 children (124 aged :5 6 months) reported in six studies was undertaken using nonlinear mixed-effects models. Neonates and infants were given either single or multiple doses of four different formulations: oral elixir, rectal solution, or triglyceride or capsular suppository. The median postnatal age of children younger than 6 months was I day (range, birth to 6 months), median postconception age was 40 weeks (range, 28-64 weeks), and median weight was 3.1 kg (range, 1.2-9.0 kg). Results: Population pharmacokinetic parameter estimates and their variability (percent) for a one-compartment model with first-order input, lag time, and first-order elimination were,is follows: volume of distribution, 66.6 1 (20%); clearance, 12.5 1/h (44%); standardized to a 70-kg person using allometric (1)/(4) power models. The volume of distribution decreased exponentially with a maturation half-life of 11.5 weeks from 109.7 1/70 kg at 28 weeks after conception to 72.9 1/70 kg by 60 weeks. Clearance increased from 28 weeks after conception (0.74 1 . h(-1) . 70 kg(-1)) with a maturation half-life of 11.3 weeks to reach 10.8 1 . h(-1) . 70 kg(-1) by 60 weeks. The absorption half-life, for the oral elixir preparation was 0.21 h (120%) with a lag dine of 0.42 h (70%), but absorption was further delayed (2 h) in premature neonates in the first few days of life. Absorption half-life parameters for the triglyceride base and capsule suppositories were 0.80 h (100%) and 1.4 h (57%), respectively. The absorption half-life for the rectal solution was 0.33 h. Absorption lag time was negligible by the rectal route for all three formulations. The bioavailability of the capsule suppository relative to elixir decreased with age from 0.92 (22%) at 28 weeks after conception to 0.86 at 2 yr of age, whereas the triglyceride base decreased from 0.86 (35%) at 28 weeks postconception to 0.5 at 2 yr of age. The relative bioavailability of the rectal solution was 0.66. Conclusions: A mean steady state target concentration greater than 10 mg/l at trough can be achieved by an oral dose of 25 mg . kg(-1) . d(-1) in premature neonates at 30 weeks' postconception, 45 mg . kg(-1) . d(-1) at 34 weeks' gestation, 60 mg . kg(-1) . d(-1) at term, and 90 mg . kg(-1) . d(-1) at 6 months of age. The relative rectal bioavailability is formulation dependent and decreases with age. Similar concentrations can be achieved with maintenance rectal doses of 25 (capsule suppository) or 30 (triglyceride suppository) mg . kg(-1) . d(-1) in premature neonates at 30 weeks' gestation, increasing to 90 (capsule suppository) or 120 (triglyceride suppository) mg . kg(-1) . d(-1) at 6 months. These regimens may cause hepatotoxicity in some individuals if used for longer than 2-3 days.