Data Analysis

As described elsewhere, the standard pharmacokinetic parameters (Cmax, tmaxs CL/F, tV; in case of the administration of a single dose: AUCt, AUCJ are usually calculated by nonparametric or parametric methods for the drug and major active metabolite(s). The parameters that are specific for repeated dose administration are the AUC during one dosing interval (AUCt) at steady state and the accumulation ratio. The latter can be directly calculated if single-dose data also is available. The reader is referred to the section "Data Analysis" on page 199 of this chapter, for a more detailed description of the calculations.

The choice of analysis of the attainment of steady state, from the trough plasma concentrations of the drug, should be stated in the protocol. If more than one dose level is investigated, an analysis of dose proportionality should be performed. It is advisable to include more than one dose, since an unexpected observation of a time-dependency in a parameter, e.g., a larger than expected AUC, may not only be caused by metabolic inhibition, but could also be due to pharmacokinetic model misspecification. For example, the terminal tV may not have been correctly determined, potentially due to lack of sensitivity in the analytical method, or the full degree of drug accumulation in tissue has not been previously achieved after single-dose administration. In addition to the analysis of the attainment of steady state (and dose proportionality if applicable), the report should contain clear graphs and tables of both individual and average data, as well as summary statistics.

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