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

Aims The aims of this study were to describe paracetamol pharmacokinetics i n neonates and infants. Methods Infants in their first 3 months of life (n=30) were randomised to s equentially receive one of three paracetamol formulations (dose 30-40 mg kg (-1)) over a 2 day period. The formulations were (a) elixir, (b) glycogelat in capsule suppository and (c) trigylceride 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 pa racetamol pharmacokinetics (n=221) and age-related pharmacokinetic changes investigated. Results Population pharmacokinetic parameter estimates and their coefficien ts of variation (CV%) for a one compartment model with first order input, l ag time and first order elimination were volume of distribution 69.9 (18%) 1 and clearance 13.0 (41%) 1 h(-1) (standardized to a 70 kg person). The vo lume of distribution decreased exponentially with a half-life of 1.9 days f rom 120 1 70 kg(-1) at birth to 69.9 1 70 kg(-1) by 14 days. Clearance incr eased from birth (4.9 1 h(-1) 70 kg(-1)) with a half-life of 3.25 months to reach 12.4 1 h(-1) 70 kg(-1) by 12 months. The absorption half-life (t(abs )) for the oral preparation was 0.13 (154%) h with a lag time (t(lag)) of 0 .39 h (31%). Absorption parameters for the triglyceride base and capsule su ppositories were t(abs) 1.34 (90%) h, t(lag) 0.14 h (31%) and t(abs) 0.65 ( 63%) h, t(lag) 0.54 h (31%), respectively. The t(abs) for elixir and capsul e suppository in children under 3 months were 3.68 and 1.51 times greater t han children over 3 months. The relative bioavailability of rectal formulat ions compared with elixir were 0.67 (30%) and 0.61 (23%) for the triglyceri de 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 1 0 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 chi ldren. A reduced dose of 75 mg ks(-1) day(-1) in an 8-year-old child is suf ficient because clearance is a nonlinear function of weight.