Population pharmacokinetics of single-dose intravenous paracetamol in children.

BACKGROUND To determine the pharmacokinetics (PK) of a new i.v. formulation of paracetamol (Perfalgan) in children ≤15 yr of age. METHODS After obtaining written informed consent, children under 16 yr of age were recruited to this study. Blood samples were obtained at 0, 15, 30 min, 1, 2, 4, 6, and 8 h after administration of a weight-dependent dose of i.v. paracetamol. Paracetamol concentration was measured using a validated high-performance liquid chromatographic assay with ultraviolet detection method, with a lower limit of quantification (LLOQ) of 900 pg on column and an intra-day coefficient of variation of 14.3% at the LLOQ. Population PK analysis was performed by non-linear mixed-effect modelling using NONMEM. RESULTS One hundred and fifty-nine blood samples from 33 children aged 1.8-15 yr, weight 13.7-56 kg, were analysed. Data were best described by a two-compartment model. Only body weight as a covariate significantly improved the goodness of fit of the model. The final population models for paracetamol clearance (CL), V(1) (central volume of distribution), Q (inter-compartmental clearance), and V(2) (peripheral volume of distribution) were: 16.51×(WT/70)(0.75), 28.4×(WT/70), 11.32×(WT/70)(0.75), and 13.26×(WT/70), respectively (CL, Q in litres per hour, WT in kilograms, and V(1) and V(2) in litres). CONCLUSIONS In children aged 1.8-15 yr, the PK parameters for i.v. paracetamol were not influenced directly by age but were by total body weight and, using allometric size scaling, significantly affected the clearances (CL, Q) and volumes of distribution (V(1), V(2)).