Comparative Pharmacokinetic Analysis
Comparative Pharmacokinetic Analysis
Study Objective: 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 C3-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 C3-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-mg 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 with the parameters decreases.
The standard two-stage method is a widely used analytic method in pharmacokinetic studies; it is relatively easy to perform and only requires software programs capable of handling single data sets. However, population-modeling techniques are being used with increasing frequency. We compared the performance of the two methods with use of the same data set.
Study Objective: 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 C3-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 C3-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-mg 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 with the parameters decreases.
The standard two-stage method is a widely used analytic method in pharmacokinetic studies; it is relatively easy to perform and only requires software programs capable of handling single data sets. However, population-modeling techniques are being used with increasing frequency. We compared the performance of the two methods with use of the same data set.
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