A model for size and age changes in the pharmacokinetics of paracetamol in neonates, infants and children

Abstract

Aims: The aims of this study were to describe paracetamol pharmacokinetics in neonates and infants.

Methods: Infants in their first 3 months of life (n = 30) were randomised to sequentially receive one of three paracetamol formulations (dose 30-40 mg kg-1) over a 2 day period. The formulations were (a) elixir, (b) glycogelatin capsule suppository and (c) triglyceride base suppository. Approximately six blood samples were taken after each dose over the subsequent 10-16 h. Data were analysed using a nonlinear mixed effect model. These neonatal and infant data were then included with data from four published studies of paracetamol pharmacokinetics (n = 221) and age-related pharmacokinetic changes investigated.

Results: Population pharmacokinetic parameter estimates and their coefficients of variation (CV%) for a one compartment model with first order input, lag time and first order elimination were volume of distribution 69.9 (18%) l and clearance 13.0 (41%) l h-1 (standardized to a 70 kg person). The volume of distribution decreased exponentially with a half-life of 1.9 days from 120 l 70 kg-1 at birth to 69.9 l 70 kg-1 by 14 days. Clearance increased from birth (4.9 l h-1 70 kg-1) with a half-life of 3.25 months to reach 12.4 l h-1 70 kg-1 by 12 months. The absorption half-life (tabs) for the oral preparation was 0.13 (154%) h with a lag time (tlag) of 0.39 h (31%). Absorption parameters for the triglyceride base and capsule suppositories were tabs 1.34 (90%) h, tlag 0.14 h (31%) and tabs 0.65 (63%) h, tlag 0.54 h (31%), respectively. The tabs for elixir and capsule suppository in children under 3 months were 3.68 and 1.51 times greater than children over 3 months. The relative bioavailability of rectal formulations compared with elixir were 0.67 (30%) and 0.61 (23%) for the triglyceride base and capsule suppositories, respectively.

Conclusions: Total body clearance of paracetamol at birth is 62% and volume of distribution 174% that of older children. A target concentration above 10 mg l-1 in approximately 50% subjects can be achieved by a dose from 45 mg kg-1 day-1 at birth and up to 90 mg kg-1 day-1 in 5-year-old children. A reduced dose of 75 mg kg-1 day-1 in an 8-year-old child is sufficient because clearance is a nonlinear function of weight.

Figure 1

Quality of fit of pharmacokinetic pooled analysis for all children over the study time. The y-axis of each panel displays the ratio of measured concentrations to those predicted from pharmacokinetic analysis. The upper panel 1a displays values from the population parameters. The lower panel 1b displays values from NONMEMs post hoc step based on values of the parameters for the specific individual. Subject 16 is shown as filled triangles to show the quality of the post hoc fit compared to the population fit.

Figure 6

Simulation of paracetamol elixir dosing in 1000 1-month-old children given 25 mg kg⁻¹ and then 15 mg kg⁻¹ 6 hourly. Children were given an age range of 0.9–1.1 months and a weight range of 3.5–4.5 kg. Variability is demonstrated using box and whisker plots. The central box represents the 50th centile. Indentations in this box indicate the median. Values outside the 97.5% centile are shown individually.

Figure 2

The weighted residuals (WRES) for each subject with values for each subject joined by vertical bars. Subject 16 (filled triangles) can be seen to deviate in a positive direction.

Figure 3

The time-concentration profile for subject 16. Post hoc estimates accurately mirror observations, but deviate from the population (typical) profile because of the low clearance in this individual.

Figure 4

The weighted residuals (WRES) for the predicted population response.

Figure 5

Pharmacokinetic parameter changes with age for pooled analysis. Neonates and infants from current study are shown as open squares. The between occasion variability for each individual is demonstrated by linking estimates with a fine line. 5a Volume of distribution changes with age. Individual predicted volumes, standardized to a 70 kg person, from NONMEMs post hoc step are plotted against age. The solid line demonstrates the nonlinear relationship between volume of distribution and age. 5b Individual predicted clearances, standardized to a 70kg person, from NONMEMs post hoc step are plotted against age. The solid line demonstrates the nonlinear relationship between clearance and age.