## Washout based on mean ± SD of t½ [Design Issues]

Hi Imph

❝ I would like to know if this method can be applied to each pharmacokinetic measurement, for example to determine the duration of the sampling (5 x t1/2) or to calculate the predose limit of 5% Cmax when the Cmax is provided in the literature under mean+/-SD.

I don't know about "every" PK parameter, but FDA use this approach to plan partial AUC as well.

For example, for methylphenidate HCl ER tablet, among other parameters, FDA requests partial AUC0--3h and AUC0--4h for fasting and fed studies, respectively. The reason was that the Tmax was 2h under fasting and 3h under fed. the standard deviation (SD) of Tmax is about 0.5h, so 2 x SD is 1h, according to FDA:

> "For Tmax, two standard deviations = 1.0; Generally, approximately 95% of observations fall within two standard deviations of the mean; Thus, since the Tmax from the immediate-release portion of this formulation is about 2 hours under fasting conditions and 3 hours under fed conditions, pAUCs calculated to 0-3 hours in a fasting BE study and 0-4 hours in a fed BE study should capture the responses of 95% of the subjects. This should provide assurance that a test and reference product will be therapeutically equivalent over the early part of the daily dosing interval, corresponding to onset of response." (see ref linked here)

This is the same as what Helmut did for t1/2 in his PPT cited in previous post.

❝ In the reference you gave, a normal distribution is assumed, but pharmacokinetic measurements do not generally follow a normal distribution but a log-normal one. Does this method still apply?

Well, Tmax is discrete so it is not normal distribution either. FDA still use it for the approximation for pAUC.

I'd use this 5 x (mean(PK) + 2xSD(PK)) instead of the empirical "7 x mean(PK)".

All the best,
Shuanghe