Population pharmacokinetic models: Effect of explicit versus assumed constant serum concentration assay error patterns upon parameter values of gentamicin in infants on and off extracorporeal membrane oxygenation

Prior authors had hypothesized (but not clearly found) an increased apparent volume of distribution (V_d) for gentamicin in neonates undergoing extracorporeal membrane oxygenation (ECMO). We chose to study the question in our own clinical setting. To develop population pharmacokinetic models of the drug, we used the nonparametric expectation and maximization population modeling method and data from 11 neonates who received gentamicin on ECMO, including 6 infants who received gentamicin both on and off ECMO for severe respiratory failure. We found an increased V_d for gentamicin on ECMO and attributed much of the difference from prior investigations to our use of an explicitly determined laboratory assay error pattern for the measured serum concentrations rather than using constant weighting of the serum level data points. For six infants, while on ECMO their median V_d was 0.748 L/kg compared with a median V_d of 0.471 L/kg after ECMO was discontinued. The median clearance of gentamicin in the six infants while undergoing ECMO was 0.239 L/h compared with 0.350 L/h after ECMO was discontinued. The median half-time (T1/2) was 9.24 h while on ECMO compared with 3.87 h when off ECMO. We conclude that while undergoing ECMO, neonates have a higher volume of distribution for gentamicin, a lower clearance, and a much longer half-life. Based on these results, for attainment of the desired peak-and-trough plasma gentamicin concentrations for infants undergoing ECMO (i.e., 5–8 and <2.0 μg/ml, respectively), we now recommend a loading dose of ∼4.3 mg/kg of gentamicin and a maintenance dose of ∼3.7 mg/kg to be given at dosing intervals of 18–24 h, followed by monitoring of serum concentrations and appropriate dose adjustments thereafter. To attain alternative goals, the model provides different loading and maintenance doses.