Bioequivalence and Bioavailability Forum • Missing values of AUCinf

Tushar.g
☆

India,
2011-02-11 08:19
(5196 d 05:16 ago)

Posting: # 6617
Views: 6,780

Missing values of AUCinf [NCA / SHAM]

Dear All,
In my firm, we performed one pilot FED study with 10 volunteers which give Ratio 116% for Ln-transformed AUCinf. In this, 3 values of AUCinf of test formulation were missing because of insufficient samples points in elimination phase after Cmax.
So again I have calculated these 3 AUCinf values manually by selecting sample points (Only 2 sample points I could select after Cmax for each of these 3 subject profile.)
I use Phoenix WinNonlin software.
By manual selection, my ratio of AUCinf directly goes to 127.5%

So can any one explain me which ratio value is more meaningful to include in final stat report?

Sorry, I know this question comes in basic knowledge of pharmacokinetic but I am little confuse.

Thanks in advance.
Regards,
Tushar

Edit: Category changed. [Helmut]

ElMaestro
★★★

Denmark,
2011-02-11 12:20
(5196 d 01:15 ago)

@ Tushar.g
Posting: # 6618
Views: 5,917

Missing values of AUCinf

Post reply

Hi Tushar,

It sounds like you do not have a procedure that describes the choice of points in the elimination phase? Would be a good idea to have one for future purposes, especially when or if you do a pivotal study.
For now, and this being a pilot, I would exclude the subjects in question and discuss it in the rpt. (missing values, lack of SOP, software bewildered -> need for thinking). you could also check the estimated CV and compare to the CV for Cmax; the AUC-CV is most often lower and if it is higher then you have an additional argument for good old-fashioned thinking.

Having said that, with a PE of 116% or higher it could quickly be game over for you. I would definitely evaluate AUCt as well; sounds to me like you in the given situation can trust AUCt better and thus base your future direction on that rather than AUCinf, even if AUCinf is a primary endpoint for you.

—
Pass or fail!
ElMaestro

Helmut
★★★

Vienna, Austria,
2011-02-11 13:54
(5195 d 23:41 ago)

@ ElMaestro
Posting: # 6619
Views: 6,211

Lambdaz - again

Post reply

My Capt’n!

❝ It sounds like you do not have a procedure that describes the choice of points in the elimination phase? Would be a good idea to have one for future purposes, especially when or if you do a pivotal study.

Remember some old posts, especially that one? My resume:

All automated procedures are restricted to methods available in the software. AFAIK all commercial programs use solely max. R²_adj. Following our discussions here only bear offers five (!) different automated methods: R²_adj (ARS), Akaike’s information criterion (AIC), Two-Times-T_max method (TTT), TTT-ARS, TTT-AIC.
We (Martin & Jack with some moral support from myself) have done simulations comparing the automated methods (our manuscript is at the bottom of the to-do-pile; volunteering co-authors with some knowledge in R are mostly welcome!). As expected especially flip-flop-PK (k_a≤k_el) is nasty. Though we have found some differences between methods in terms of bias for λ_z, the differences diminish when it comes to the calculation of AUC_∞.
There is a rank order where automated methods might fail: 1 compartment < 2+ compartments < MR formulations (especially with “flat” peaks) < pulsed formulations. I work a lot on the latter and don’t use the automated method even as an initial guess…
All (!) papers and textbooks emphasize the importance of inspection of automated fits and corrective measures if deemed necessary (=eye-balling).

In other words: no rule rulez. But: it must be clear, that the selection of time points is not driven by the “desire” to obtain AUC_t ≥80% of AUC_∞. Preferably estimation of λ_z is done blinded for treatment – before NCA!
I would not be so radical like Maria Durisova stating at David's list:

AUC_t to AUC_inf ratio is meaningless. The reason for this is that time "t" is selected by a pharmacokinetician, consequently AUC_t to AUC_inf depends on the pharmacokinetician choice.

—
I could be wrong, but… :-D

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Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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ElMaestro
★★★

Denmark,
2011-02-11 15:05
(5195 d 22:30 ago)

@ Helmut
Posting: # 6620
Views: 5,774

Lambdaz - again

Post reply

Ahoy HS

just to clarify:
I argue in favour of eye-balling (of elimination constants, chromatograms, ECGs and even the transaction slips you get in the supermarket; sometimes they forget to tell the computer that Emmentaler is on sale).
And even of QC'ing point elim. points / R-R-intervals / chrom. areas 100%.

There is some degree of rhetorics involved here. Some companies say they aim for 0% manual corrections. Some companies say it is deffo necessary to do manual corrections. In my opinion they mean exactly the same but achieve their goal in different manners. In the first case the companies for instance seek to somehow eliminate the cases where the computer cannot make a qualified choice; in the last case they just override where it's deemed necessary.
In both cases human intervention (and subjectivity) comes into play one way or another, all with my blessing.

—
Pass or fail!
ElMaestro