POPULATION PHARMACOKINETIC MODELS - EFFECT OF EXPLICIT VERSUS ASSUMEDCONSTANT 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 ap parent volume of distribution (V-d) for gentamicin in neonates undergo ing extracorporeal membrane oxygenation (ECMO). We chose to study the question in our own clinical setting. To develop population pharmacoki netic models of the drug, we used the nonparametric expectation and ma ximization population modeling method and data from 11 neonates who re ceived gentamicin on ECMO, including 6 infants who received gentamicin both on and off ECMO for severe respiratory failure. We found an incr eased V-d for gentamicin on ECMO and attributed much of the difference from prior investigations to our use of an explicitly determined labo ratory assay error pattern for the measured serum concentrations rathe r than using constant weighting of the serum revel data points. For si x 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 cl earance of gentamicin in the six infants while undergoing ECMO was 0.2 39 L/h compared with 0.350 Lih after ECMO was discontinued. The median half-time (T-1/2) was 9.24 h while on ECMO compared with 3.87 h when off ECMO. We conclude that while undergoing ECMO, neonates have a high er volume of distribution for gentamicin, a lower clearance, and a muc h longer half-life. Based on these results, for attainment of the desi red peak-and-trough plasma gentamicin concentrations for infants under going ECMO (i.e., 5-8 and <2.0 mu g/ml, respectively), we now recommen d a loading dose of similar to 4.3 mg/kg of gentamicin and a maintenan ce dose of similar to 3.7 mg/kg to be given at dosing intervals of 18- 24 h, followed by monitoring of serum concentrations and appropriate d ose adjustments thereafter. To attain alternative goals, the model pro vides different loading and maintenance doses.