Comparison of population pharmacokinetic models for gentamicin in spinal cord-injured and able-bodied patients

Population pharmacokinetic models for gentamicin were developed by using data obtained from 29 spinal cord-injured patients and 11 able-bodied control patients. With a one-compartment model, the population parameters were clearance (CL), volume of distribution (V), and their associated variances. Parameter estimates were found by using the computer program NPEM and by the standard two-stage (STS) method. NPEM uses a nonparametric approach incorporating the expectation maximization algorithm to evaluate a joint probability density function at 900 intersections over a bivariate grid. In contrast, the STS method requires conventional assumptions of normality for the underlying distributions. For NPEM, the mean CL was 97.6 ml/h/kg of body weight (coefficient of variation, 33.0% in the spinal cord-injured patients and 67.8 ml/h/kg +/- 28.2% in the able-bodied patients; the mean V was 0.31 liter/kg +/- 32.3% in the spinal cord-injured patients and 0.23 liter/kg +/- 15.8% in the able-bodied patients. For STS, the mean CL was 101.0 ml/h/kg +/- 37.5% in the spinal cord-injured patients and 65.0 ml/h/kg +/- 33.8% in the able-bodied patients; the mean V was 0.29 liter/kg +/- 34.0% in the spinal cord-injured patients and 0.21 liter/kg +/- 21.0% in the able-bodied patients. Although the means and variances found by NPEM and the STS method were similar, the NPEM analysis revealed that the distributions of CL and V, even after they were linked to weight, were positively skewed and kurtotic. The cumulative distribution functions for CL (P < 0.001) and V (P < 0.001) in spinal cord-injured patients were different from those in able-bodied patients. Unique population models are required for the initial dosage selection for spinal cord-injured patients. Future approaches for developing population models should allow the linkage of structural parameters to multiple patient covariates.