In this dissertation a methodology is proposed for simultaneously evaluating the population bioequivalence (PBE) of a generic drug to a pre-licensed drug, or the bioequivalence of two formulations of a drug using multiple correlated pharmacokinetic metrics. The univariate criterion that is accepted by the food and drug administration (FDA) for testing population bioequivalence is generalized. Very few approaches for testing multivariate extensions of PBE have appeared in the literature. One method uses the trace of the covariance matrix as a measure of total variability, and another uses a pooled variance instead of the reference variance. The former ignores the correlation between the measurements while the later is not equivalent to the criterion proposed by the FDA in the univariate case, unless the variances of the test and reference are identical, which reduces the PBE to the average bioequivalence. The confidence interval approach is used to test the multivariate population bioequivalence by using a parametric bootstrap method to evaluate the 100% (1-alpha) confidence interval. The performance of the multivariate criterion is evaluated by a simulation study. The size and power of testing for bioequivalence using this multivariate criterion are evaluated in a simulation study by altering the mean differences, the variances, correlations between pharmacokinetic variables and sample size. A comparison between the two published approaches and the proposed criterion is demonstrated. Using nonlinear models and nonlinear mixed effects models, the multivariate population bioequivalence is examined. Finally, the proposed methods are illustrated by simultaneously testing the population bioequivalence for AUC and Cmax in two datasets.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-2983 |
| Date | 17 November 2009 |
| Creators | Dahman, Bassam |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © The Author |
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