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R W Jelliffe

Publications and source records attributed to R W Jelliffe.

At least 19 recordsLinked to original sources
PubMed1992

Population pharmacokinetics of gentamicin. Use of the nonparametric expectation maximisation (NPEM) algorithm.

A new nonparametric expectation maximisation (NPEM) algorithm for the estimation of population pharmacokinetic parameter values was evaluated. The algorithm, in the form of a personal computer program, was used to compute population pharmacokinetic parameter densities of gentamicin in a group of 9 patients with indicators of malnutrition. The 1-compartment parameter values for clearance (CL), volume of distribution (Vd) and elimination rate constant (k) were compared with values generated using a standard 2-stage (STS) approach. NPEM was used with a full data set (72 gentamicin concentrations) and a sparse data set (only peak and trough concentrations for each patient; 18 in total). There were no differences in parameter value estimations between the STS and NPEM with all the data (p greater than 0.05) or with the sparse data (p greater than 0.05). Mean parameter value estimates from the STS and NPEM (with sparse data) were used as a priori data sets in the USC*PACK gentamicin Bayesian program to predict concentrations in 8 subsequent patients with similar indicators of malnutrition. There were no differences in predicted gentamicin concentrations between STS (3.75 +/- 2.06 mg/L) and NPEM (3.75 +/- 2.17 mg/L). NPEM was able to generate population pharmacokinetic parameter values for gentamicin in a defined population of patients using sparse routine clinical data. It was also shown to function with only a single data point per patient.

Aged↗
PubMed1991

Gentamicin population pharmacokinetic models for low birth weight infants using a new nonparametric method.

Availability of personal computer programs for control of drug regimens has stimulated interest in modeling population pharmacokinetics. In this study, we found parameter values for gentamicin in two infant populations with low birth weights. The models were developed by use of a parametric (i.e., standard two-stage algorithm) and with a new nonparametric expected maximum algorithm. Data for the two populations (i.e., infants less than or equal to 31 weeks' and greater than 31 but less than or equal to 34 weeks' gestational age) were obtained from infants admitted to the University of Texas Medical Branch intensive care nursery between August 1, 1988, and July 31, 1989. The new nonparametric method was demonstrated to be not only the equal of the standard two-stage method for population modeling but better, especially in use of sparse data sets (e.g., single serum levels). It also obviates the need for selecting proper starting conditions for the least-squares fitting procedure used in the standard two-stage method.

Computer Simulation↗
PubMed1991

Sodium hyaluronate as a carrier for intravitreal gentamicin. An experimental study.

Fifty mcg of gentamicin was combined with saline or with 0.8% sodium hyaluronate and injected into the vitreous cavity of rabbit eyes with moderate to severe Staphylococcus aureus endophthalmitis. Endophthalmitis was controlled in 9 of 10 eyes. There was no evidence of toxicity with either treatment regimen. Although the clearance study demonstrated statistical differences at all time points studied, the half-lives of both treatment regimens were similar (3.3 h for aqueous gentamicin and 3.6 h for sodium hyaluronate/gentamicin). These results suggest that the vitreous played a role in keeping the aqueous gentamicin in the eye for a longer time, as similar half-lives were shown with both types of treatment. Thus, if a vitrectomy has to be done for the treatment of endophthalmitis, as much as possible of the vitreous should be left in situ to maintain the drug for longer periods in the eye. Also, if it is necessary to remove all vitreous during vitrectomy, it may be more effective to administer the drug with sodium hyaluronate so as to prolong its action inside the eye.

Animals↗
PubMed1991

In vitro and in vivo studies with sodium hyaluronate as a carrier for intraocular gentamicin.

We compared the in vitro growth of common intraocular pathogens Staphylococcus aureus, Staphylococcus epidermidis and Pseudomonas aeruginosa in rabbit vitreous and in sodium hyaluronate (SH) with and without gentamicin. The minimal inhibitory concentration for gentamicin/SH was 0.5, 0.062 and 2.0 mcg/ml for these pathogens, respectively. After posterior capsulotomy, P. aeruginosa was inoculated into the anterior vitreous and all 15 untreated eyes developed endophthalmitis. In a similar group, aqueous gentamicin administered in the anterior chamber reduced the incidence of endophthalmitis to 10 of 15 eyes. Under similar circumstances, the SH/gentamicin combination lowered the incidence of endophthalmitis significantly to 4 of 15 eyes. The half-life of aqueous gentamicin was 0.9 h, which was shorter than the 2.2 h for SH/gentamicin combination. These results suggest that SH may be a useful carrier for intraocular drug therapy.

Animals↗
PubMed1991

Individualising gentamicin dosage regimens. A comparative review of selected models, data fitting methods and monitoring strategies.

The various components required for individualising clinical drug dosage regimens are reviewed, including a study of 3 types of fitting procedures, 2 types of gentamicin pharmacokinetic model and the utility of D-optimal times for obtaining serum gentamicin concentrations. The combination of the current Bayesian fitting procedure, the kslope pharmacokinetic model [in which the elimination rate constant (kel) can change from dose to dose with changing creatinine clearance] and the explicit measurement of the assay error pattern yielded predictions of future serum gentamicin concentrations which were (a) slightly better than those found using weighted nonlinear least squares; (b) somewhat better than those found with Bayesian fitting and a fixed-kel model; (c) better than those found using the traditional linear regression fitting procedure and a fixed kel model. D-Optimally timed pairs of concentrations also predicted future concentrations at least as well, and more cost effectively.

Data Interpretation, Statistical↗
PubMed1991

The USC*PACK PC programs for population pharmacokinetic modeling, modeling of large kinetic/dynamic systems, and adaptive control of drug dosage regimens.

Programs for PC's and compatibles provide nonparametric (NPEM) population pharmacokinetic modeling, BOXES for compartments and arrows for pathways, to make large kinetic and dynamic models, and clinical software for Bayesian adaptive control of drug dosage regimens, with D-optimal sampling strategies and explicit determination of assay error patterns.

Bayes Theorem↗
PubMed1990

Application of a Bayesian method to monitor and adjust vancomycin dosage regimens.

A Bayesian method for monitoring vancomycin concentrations and adjusting regimens in patients with unstable renal function by using a two-compartment population model was evaluated with a personal computer. The population model was derived from data from 12 cardiac outpatients who received single doses of vancomycin. The performance of the method was then tested in 27 acutely ill patients who received multiple doses of vancomycin. Significant renal impairment was observed in 15 patients. Renal function changed in 15 patients. The vancomycin concentrations in the patients with changing renal function were not at steady state during the observation times. Two concentrations in serum (peak and then trough, or trough and then peak) were fitted along with the population model to individualize the parameter values for each patient. All the subsequent concentrations in serum for each patient were then predicted by using the parameter values for each patient. Future concentrations of 118 serum samples were predicted. The mean absolute prediction error was 3.6 +/- 4.5 micrograms/ml, and the mean prediction error was -0.7 +/- 5.3 micrograms/ml. These results confirm that a two-compartment pharmacokinetic model can be sufficiently individualized with the knowledge of just two concentrations of drug in patient serum; it is possible to predict closely subsequent concentrations in serum, and dosing regimens for individual patients can be well adjusted to achieve the chosen therapeutic goals.

Adult↗
PubMed1990

Modeling, adaptive control, and optimal drug therapy.

Drug therapy, its clearly development, and the advent of pharmacokinetic models are described, from the original work of Teorell, through that of Augsberger and Kruger-Thiemer, to the present. Adaptive control of such models, long known in engineering, began in therapeutics with methods for linear and nonlinear least-squares regression, and has progressed to the Maximum Aposteriori Probability (MAP) Bayesian method. Strategies for optimal monitoring of serum concentrations are described and their clinical results briefly evaluated. Lastly, the new method of Approximate Optimal Closed-Loop (AOCL) control is described, in which the therapeutic regimen is used at the same time to probe (learn about) the patient's model approximately optimally. The new method considers the expected values of planned future serum concentrations (or other responses), in addition to the traditional measurement of past serum concentrations. This should optimize the process of learning about a patient's model while treating him at the same time.

Bayes Theorem↗
PubMed1987

Drug-receptor relationships, selection of therapeutic goals, and adaptive control of pharmacokinetic systems.

Drug-receptor relationships are governed by a host of environmental and physiological influences, which reduce the predictability of the therapeutic response to an administered dose of a drug. The management of patient therapy is aided by models that encompass the broadest aspects of the situation, from the probabilistic aspects of drug administration to the accuracy of the assay procedures for evaluating therapeutic efficacy.

Aminoglycosides↗
PubMed1984

Clinical studies with computer-assisted initial lidocaine therapy.

A randomized prospective study compared achievement and maintenance of therapeutic plasma concentrations in patients receiving computer-assisted (CA) initial lidocaine hydrochloride therapy, designed pharmacokinetically to achieve and maintain a chosen plasma concentration, v conventional lidocaine therapy (CT). A separate audit of outcome was also conducted. The CA regimens provided more effective concentrations in the first hour than did CT, 2.65 v 1.5 micrograms/mL average. In the audit, ventricular fibrillation occurred in two of 78 CA v eight of 78 CT patients. Dosage adjustments were required in two CA patients v 33 CT patients. The CA therapy improved therapeutic precision, reduced dosage adjustments, and may have improved safety during initial lidocaine therapy before fitting to plasma concentration data for subsequent feedback. An improved clinical computer program now also fits to plasma concentration data. It is accessed and used routinely by hospitals over an international time-sharing network.

Aged↗
PubMed1982

N-Acetylprocainamide kinetics and clinical response during repeated dosing.

Kinetics of and clinical responses to N-acetylprocainamide (NAPA) were evaluated in 10 patients with chronic ventricular arrhythmias who had not responded to usual doses of currently available antiarrhythmic drugs. Kinetic data analysis was by measured NAPA concentrations (n = 149) collected during repeated dosing. Response was evaluated with serial 24-hr ambulatory ECGs. An a priori kinetic model based on earlier studies predicted NAPA concentrations well (r = 0.94, SEE = 3.6 mg/l). The capability for defining patient-specific estimates for drug disposition with six or seven serum concentrations measured at the outset of therapy was subsequently confirmed with larger data sets from the same patients. Mean values for elimination rate (0.082 hr -1 +/- 0.017) and volume of distribution (1.25 l/kg +/- 0.28) were of the same order as in earlier single-dose studies. A substantial degree of interpatient and intrapatient variability in the absorption rate for NAPA was observed. NAPA was not found to be clinically effective in any of the 10 patients, although two patients demonstrated a greater than 70% reduction in frequency of premature ventricular contractions. There were adverse effects in all patients, which frequently required dose reduction or cessation of therapy. In this group of patients with resistant arrhythmias, NAPA was no more effective than baseline therapy, and adverse effects often limited complete evaluation. The kinetic analysis demonstrated the feasibility of a strategy for developing patient-specific kinetic models that may have applications to other antiarrhythmic drugs.

Acecainide↗