Data Analysis

Standard pharmacokinetic parameters (Cmax, tmax, AUQt, AUC„, CL/F, 11/2) are calculated by nonparametric or parametric methods for the intact drug and major active metabolite(s). The reader is referred to the section Data Analysis on page 199 of this chapter, for a more detailed description of the calculations. The parameters describing exposure (Cmax and AUC) or apparent oral clearance (CL/F) are of most interest for orally administered drugs. For short-acting drugs, such as agents for the treatment of insomnia or acute pain, the intial exposure (truncated AUC up to Cmax or Cmax) may be a more relevant descriptor for dose proportionality than AUC„.

These parameters are graphically displayed vs the administered dose, where a straight line indicates linear pharmacokinetics over the studied dose range. It is recommended that the analysis is performed after dose normalization of the parameters has been performed. There is no formal regualtory recommendations regarding the method of choice. The interested reader can find points to consider regarding the statistical analysis to determine dose proportionality in an article by Gough et al. [22], where a comparison of the performace of different statistical methods was investigated. The data should also be analyzed regarding the similarity of the other pharmacokinetic parameters at the different dose levels, a shift in terminal half-life or tmax between doses may need additional attention, and the potential clinical relevance of any dissimilarities in these parameters between different doses should be considered.

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