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  • 1
    Electronic Resource
    Electronic Resource
    Population Pharmacokinetic Modeling: The Importance of Informative Graphics (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1845-1855 
    Details
    ISSN: 1573-904X
    Keywords: graphics ; MLR ; GAM ; TBM ; diagnostics ; jackknife ; population pharmacokinetics ; subpopulations
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The usefulness of several modelling methods were examined in the development of a population pharmacokinetics model for cefepime. Methods. The analysis was done in six steps: (1) exploratory data analysis to examine distributions and correlations among covariates, (2) determination of a basic pharmacokinetic model using the NON-MEM program and obtaining Bayesian individual parameter estimates, (3) examination of the distribution of parameter estimates, (4) multiple linear regression (MLR) with case deletion diagnostics, generalized additive modelling (GAM), and tree-based modelling (TBM) for the selection of covariates and revealing structure in the data, (5) final NONMEM modelling to determine the population PK model, and (6) the evaluation of final parameter estimates. Results. An examination of the distribution of individual clearance (CL) estimates suggested bimodality. Thus, the mixture model feature in NONMEM was used for the separation of subpopulations. MLR and GAM selected creatinine clearance (CRCL) and age, while TBM selected both of these covariates and weight as predictors of CL. The final NONMEM model for CL included only a linear relationship with CRCL. However, two subpopulations were identified that differed in slope and intercept. Conclusions. The findings suggest that using informative graphical and statistical techniques enhance the understanding of the data structure and lead to an efficient analysis of the data.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016215116835
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  • 2
    Electronic Resource
    Electronic Resource
    Evaluation of theophylline pharmacokinetics in a pediatric population using mixed effects models (1989)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 17 (1989), S. 141-168 
    Details
    ISSN: 1573-8744
    Keywords: theophylline kinetics ; population pharmacokinetics ; NONMEM ; age and kinetics ; gender and kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Routine clinical pharmacokinetic data collected prospectively from pediatric patients receiving theophylline were analyzed using the NONMEM (nonlinear mixed effects model) digital computer program. A total of 314 measured serum theophylline concentrations (STCs) were obtained from 84 hospitalized patients ranging in age from 4 months to 15.2 years with the majority of patients between the ages of 1 and 8 years. Fifty-six percent were male. The race/ethnicity distribution was 71.4% Latin, 15.5% black, 11.9% Caucasian, and 1.2% (one subject) Pakistani. Of the total number of observed STCs, 16.2% reflected some degree of outpatient dosing. The pharmacokinetic model used was a one-compartment open model with either zero-order or first-order absorption and first-order elimination. Age was the most important determinant of theophylline clearance (Cl);weight was inferior to age and did not statistically improve the model (p〉0.005when combined with age. Total Clincreased by 10%/year over the age range of 1 to 15 years of age. Black race and male gender were associated with higher Clvalues: for a given age, Clwas 34% higher for blacks than the reference population composed of the remaining patients, and Clfor males was 25% higher than that for females. The volume of distribution (Vdfor the population was estimated to be 0.62 L/kg. The interindividual variability in Cland Vdexpressed as coefficients of variation were 19 and 28%, respectively. The residual intraindividual error variance corresponded to a standard deviation of 2.8 μg/ml. The STCs that represented some degree of outpatient dosing were 21 % lower than those reflecting only inpatient dosing. Alternate models that include weight as a determinant of theophylline clearance are also provided. The NONMEM method of determining population pharmacokinetics is well suited to the pediatric population since it does not require a large number of STCs per patient. In this study a mean of only 3.7 STCs per patient were utilized to provide information which should prove useful in the design and adjustment of theophylline dosage regimens in children.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059025
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    Paper (German National Licenses)
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