Age and size are the major covariates for prediction of levobupivacaine clearance in children
Summary
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 Tmax in neonates and young infants.
