Bioequivalence and Bioavailability Forum

Dear Ohlbe!

❝ Hey, that's a nice post and a nice demonstration.

Thanks!

❝ By the way, nice new home page, too.

Oh, I just refurbished the CSS; that's the wonderful thing with valid (X)HTML – if you want to change the layout of an entire website, only a single file has to be modified. Theoretically.

❝ ❝ It’s definitely better to go with Method #5, which is standard according to the WHO, European any many other countries’ guidelines.

❝ […] Anyway the EU BE guideline recommends the use of AUC_t as the "most reliable estimate of the extent of absorption" anyway.

Without going into my files - the main parameter for extent of BA was changed from the 1992 version in 1998; and I’m still happy with it. There are a lot of papers published demonstrating for partial AUCs that beyond 2–4× t_max point estimates do not essentially change any more; only variability increases. The worst metric in terms of variability is AUC_0-∞.

❝ I couldn't find it either in the WHO guideline, which mentions "Clast" and defines it as "last measurable concentration".

OK, the entire paragraph reads:

Area under the plasma/serum/blood concentration–time curve from time zero to time t (AUC_0–t), where t is the last sampling time point with a measurable concentration of the API in the indi­vi­du­al formulation tested. The method of calculating AUC-values should be specified. In general AUC should be calculated using the linear/log trapezoidal integration method. The exclusive use of compartmental-based parameters is not recommended.

So the recommendation goes with Method #1 (not #2!).

Further down:

AUC_0–t and C_max are considered to be the most relevant parameters for assessment of bio­equi­va­lence. In addition it is recommended that the following parameters be estimated:
- area under the plasma/serum/blood concentration–time curve from time zero to time infinity (AUC_0-∞) representing total exposure, where AUC_0-∞ = AUC_0–t + C_last/β; C_last is the last mea­sur­able drug concentration and β is the terminal or elimination rate constant calculated according to an appropriate method;

It’s nice to see AUC_0–t as the recommended metric – but it’s a pity to go with Method #4 for extrapolation.

❝ Is there any recommendation I have missed in EU or WHO guideline, or made at a conference ?

Not in the guidelines; in papers, workshops & conferences – yes.
Perhaps I will post a little collection the next days.

❝ I couldn't say about BA trials (where there would be more modelling anyway) but I think I've only seen once a BE trial using Method #5.

Really? Was it one of my hundreds?
OK, to be more serious – I used Method #4 in only 3 out of >500 studies, because I failed in convincing these sponsors in the reasonability of applying Method #5.
Method #5 is my standard and also in a couple of CROs which are rather more scientifically than “cook­book”-driven in their evaluations. On the other hand I never got any deficiency letter claiming that I should recalculate my results obtained with Method #5 by Method #4.
Just the fact that Method #5 is implemented in commercial software packages (WinNonlin, Kinetica) gives you a hint that it must be used by somebody – except myself.