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- Title
Comparative Pharmacokinetic Analysis by Standard Two-Stage Method versus Nonparametric Population Modeling.
- Authors
Tam, Vincent H.; Preston, Sandra L.; Drusano, George L.
- Abstract
To compare the two-stage method, a widely used analytical method in pharmacokinetic studies, with nonparametric population modeling by using the same data set for determining the oral bioavailability of ribavirin. Design. Pharmacokinetic analysis. Setting. Clinical research center. Material. Oral bioavailability data of ribavirin determined previously in six healthy adults. Intervention. After ([sup13]C[sub3])-ribavirin 150 mg intravenously and unlabeled ribavirin 400 mg orally had been given 1 hour apart, serial serum and urine samples were obtained for up to 169 hours. Concentrations of ([sup13]C[sub3-]) ribavirin and unlabeled ribavirin in serum and urine were determined by a high-performance liquid chromatography tandem mass spectrometric method. Measurements and Main Results. Serum and urine concentration-time profiles were comodeled with a three-compartment model. The analysis was performed again by using the nonparametric population analysis technique. Serum ribavirin concentrations underwent Monte Carlo simulation for 1000 subjects receiving a single 600-m-g oral dose. Both methods were similar in determining the mean ± SD bioavailability (51.8 ± 21.8% by the two-stage method vs 54.8 ± 16.4% by nonparametric modeling, p=0.79), However, the estimates of dispersion of model parameters and simulated drug exposures were substantially reduced by the population-modeling technique, as it takes into account covariance among model parameters and intersubject variability. Conclusion. Although the study sample was small, our parallel analyses of the same data set clearly demonstrated that more precise parameter estimates are likely to result with the population-modeling technique. Having accurate and precise estimation of population pharmacokinetic parameters and their true variances is crucial, as, at any dose, there will be a lower probability of encountering a concentration-driven toxicity because of fewer outliers as the variance associated...
- Subjects
PHARMACOKINETICS; POPULATION; NONPARAMETRIC statistics; BIOAVAILABILITY; RIBAVIRIN
- Publication
Pharmacotherapy, 2003, Vol 23, Issue 12, p1545
- ISSN
0277-0008
- Publication type
Article
- DOI
10.1592/phco.23.15.1545.31969