Bioequivalence and Bioavailability Forum

Hi all,

I hope you guys are enjoying the Olympic Games.

I have a few questions with regard to the following paragraph from EMA's BE guideline:

In case of non-linear pharmacokinetics (i.e. not proportional increase in AUC with increased dose) there may be a difference between different strengths in the sensitivity to detect potential differences between formulations. In the context of this guideline, pharmacokinetics is considered to be linear if the difference in dose-adjusted mean AUCs is no more than 25% when comparing the studied strength (or strength in the planned bioequivalence study) and the strength(s) for which a waiver is considered. In order to assess linearity, the applicant should consider all data available in the public domain with regard to the dose proportionality and review the data critically. Assessment of linearity will consider whether differences in dose-adjusted AUC meet a criterion of ± 25%.

There are a lot of discussion on the topic of linearity/proportionality in the forum, however, the only post closer to my question is this one and it did answer all my questions.

Here's a bit background:

We have an old product in the market that was marketed based on bibliographic application. Since the product is really old, few PK info. was available. After some discussion with the regulatory we decided to do a dose proportionality (DP) study. I have some experience on DP with new chemical entity where at least 5-6 strengths were used and power model was applied based on Smith's article.

However, for this product, only 2 strengths exist. x and 2x mg. I guess power model doesn't make any sense here.

The CRO send us a protocol based on standard 2x2 BE design with standard 80-125% BE criteria for 90% confidence interval of Cmax, AUCt and AUCinfinity to conclude dose proportionality.

It doesn't seems right to me. So here are my questions:

1. what does +-25% means in the guideline mentioned above? in term of log-transformed or normal scale?

In normal scale, if one dose gives AUC= 100, then the AUC of the other dose (adjusted by dose) should be within 100 +- 100*0.25 = 75 to 125?

In log-scale as in BE, 80-125% criteria corresponds log-transformed difference +-0.22314... (so 100*exp(+-0.22314...) will give 80-125%. so does this mean we can use 0.25 instead and back-transform to normal value as interval of 100*exp(+-0.25) which is 77.88 - 128.4%? That would be weird.

2. I think AUCt alone should be used as criteria (difference of Cmax may obtained for additional information purpose but not as a criterion, AUCinf is not a required parameter in Europe.) as indicated by guideline and also suggested by Martin in other post.

3. In general, how would you design the study if I may ask?

regards,

Shuanghe,