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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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A study was conducted to determine the effect of metoclopramide on the disposition of dantrolene in patients with spinal cord injury (SCI) and in neurologically intact, able-bodied volunteers. Fifteen serum samples each were collected from 6 able-bodied volunteers and 13 patients with SCI (7 paraplegics, 6 quadriplegics) in a prospective, open-label, pharmacokinetic study of a single 100-mg oral dose of dantrolene. After a washout period, a single 10-mg intravenous dose of metoclopramide was given along with dantrolene to the patients with SCI only, and the study was repeated in sequential, crossover fashion. Concentrations of dantrolene were measured by a high-performance liquid chromatography (HPLC) assay. Numerical integration was used to calculate area under the curve (AUC) and mean residence time (MRT). Differences were studied using paired and two-sample, nonparametric tests, with 0.05 as the significance level. Without metoclopramide, the AUC of dantrolene was larger in able-bodied volunteers than in patients with SCI, and the MRT of dantrolene was similar both groups. When patients with SCI received metoclopramide before treatment with dantrolene, the median increase in the AUC for dantrolene was 57%, with no change in MRT. This pharmacokinetic interaction is probably attributable to augmented absorption and could alter the pharmacologic action of dantrolene. Concurrent treatment of patients with SCI with metoclopramide and dantrolene should be accompanied by careful surveillance to avoid toxicity and preserve efficacy.

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