Sample reuse simulation in optimal design for Tmax in pharmacokinetic experiments |
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Authors: | Jixian Wang |
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Institution: | University of Dundee, UK |
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Abstract: | T max and C max are important pharmacokinetic parameters in drug development processes. Often a nonparametric procedure is needed to estimate them when model independence is required. This paper proposes a simulation-based optimal design procedure for finding optimal sampling times for nonparametric estimates of T max and C max for each subject, assuming that the drug concentration follows a non-linear mixed model. The main difficulty of using standard optimal design procedures is that the property of the nonparametric estimate is very complicated. This procedure uses a sample reuse simulation to calculate the design criterion, which is an integral of multiple dimension, so that effective optimization procedures such as Newton-type procedures can be used directly to find optimal designs. This procedure is used to construct optimal designs for an open one-compartment model. An approximation based on the Taylor expansion is also derived and showed results that were consistent with those based on the sample reuse simulation. |
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Keywords: | Non-linear mixed models Optimal design Optimization Sample reuse Simulation T max |
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