Exploratory Evaluation of Time-invariant Steady-state Pharmacokinetics

Step Mean CV % Median Med/ 100 mg Mean CV % Median Med/ 100 mg Mean CV % Median 

Total relative plasma clearance (CL/f) was found to decrease for the reasons mentioned above, leveling off at the 100 mg dose. 

Comparing the data from the seven dose groups synoptically, it can be seen that the dose normalized exposure [AUCinf] shows much fewer differences for the medians than the dose normalized peak values [Cmax] (see Table 1). The variability [CV %] is greater than 50 % for nearly all of these observations. 

As described, the assessment of the dose linear-ity/proportionality is hampered in this case by the fact that for the lower doses the profile is not complete assessable, that obviously at the highest dose the resorption is limited, and that the used suboptimal formulation generates a lot of variability. Nevertheless, the example shows that even in this case predictions to support dose escalation were possible, and were even very helpful in that specific study. 

Exploratory Evaluation of Time-invariant Steady-state Pharmacokinetics 

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II.S.2 Exploratory Evaluation of Time-invariant Steady-state Pharmacokinetics... 

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