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 ®rst 3 months of life (n=30) were randomised to sequentially receive one of three paracetamol formulations (dose 30±40 mg kg x1 ) 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 coef®cients of variation (CV%) for a one compartment model with ®rst order input, lag time and ®rst order elimination were volume of distribution 69.9 (18%) l and clearance 13.0 (41%) l h x1 (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 x1 at birth to 69.9 l 70 kg x1 by 14 days. Clearance increased from birth (4.9 l h x1 70 kg x1 ) with a halflife of 3.25 months to reach 12.4 l h x1 70 kg x1 by 12 months. The absorption halflife (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 suppositories 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 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 x1 in approximately 50% subjects can be achieved by a dose from 45 mg kg x1 day x1 at birth and up to 90 mg kg x1 day x1 in 5-year-old children. A reduced dose of 75 mg kg x1 day x1 in an 8-year-old child is suf®cient because clearance is a nonlinear function of weight.

Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance

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“…Allometric scaling has a strong theoretical and empirical basis with a PWR exponent of 0.75 for clearance and 1 for distribution volume [10][11][12][13][14]. We have chosen a standard weight of 70 kg to enable comparison with adult values and other paediatric studies.…”

Population Pharmacokinetics of Amphotericin B Lipid Complex in Neonates

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