Age and size are the major covariates for prediction of levobupivacaine clearance in children

Background: We aimed to identify and quantify major factors describing the variability of levobupivacaine clearance in children. Methods: Data from three published studies were used to estimate population pharmacokinetics of levobupivacaine in children who were given epidural regional blockade. Covariate analysis included weight and postnatal age (PNA). Time-concentration profile analysis was undertaken using nonlinear mixed effects models. A one-compartment linear disposition model with first order input and first order elimination was used to describe the data. Results: There were 86 children (weight 9.4, SD 5.5, range 1.9-23 kg; PNA 16.1, SD 22.7, range 0.6-98 months). The population parameter estimate for volume of distribution (V) was 189 l.70 kg(-1). Clearance (CL) was 5.8 l.h(-1).70 kg(-1) at 1-month PNA and increased with a maturation half-time of 2.3 months to reach 80% of the mature value (22.1 l.h(-1).70 kg(-1)) by 6-month PNA. The between subject variability (BSV) for V and CL were 48.5% and 35.2%. Overall, 85.7% of the variability of CL was predictable. Weight alone explained 62.4% and the addition of PNA a further 23.3%. Overall, 69.2% of the variability of V was predictable and attributable to weight; V did not change with age in this cohort. The absorption half-time decreased from 0.36 h at 1-month PNA to 0.14 h (CV 48.1%) at 6-month PNA with a maturation half-time of 0.8 months. Conclusions: Size and PNA are the major contributors to clearance variability in children. These covariates should be considered when establishing safe epidural infusion regimens. Reduced clearance and slower absorption half-time contribute to delayed T-max in neonates and young infants.