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

Abstract

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 (K, 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 mI/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 Vwas 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 Vwas 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.Population pharmacokinetic methods are used to study pharmacokinetic processes by analyzing pooled data sampled from some underlying population of interest (1,5,12,15,19,28). Population approaches provide mean parameter estimates and allow variances to be partitioned into withinindividual and between-individual components. In addition, population approaches allow pharmacokinetic parameters to be linked to informative covariates, and this may further reduce the variance terms in the models. Examples of informative covariates are age, gender, ethnicity, body size, health-disease status or markers, environmental exposures, and genetic characteristics. Properly constructed population pharmacokinetic models are useful for selecting rational dosing regimens of drugs for individual patients.The standard two-stage (STS) method provides estimates of population parameters in stages (25,27). In the first stage, ordinary least-squares regression parameters are estimated from data from each individual. In the second stage, population parameters are estimated by pooling the individual estimates. This method, like the computer program NONMEM, which utilizes extended least squares to f...

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Acute Spinal Cord Injury Induces Genetic Damage in Multiple Organs of Rats

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