Bioequivalence and Bioavailability Forum

Oh,
did the Saudi FDA also try to get you to do the one-week tuition?
How was it? I would have loved to go, but couldn't for a number of reasons. But then again, Belgian sailors ain't of much use in the desert.

EM.

Dear D. Labes,

❝ 1. Option: Exclude subject

❝ 2. Option: Use AUC(0-48)

❝ 3. Option: Extrapolate to 72h (C(calc.)=5.69 using log-lin regression with * points) and calculate then AUC (result =595.85).

Whichever option you select, you can be sure there will be an Agency to say it was the wrong one... (At least the French Agency, I guess )

❝ 1. Option: Exclude subject

They will hate that... They will be afraid that you may pretend to have broken a tube in order to remove a subject with "annoying" results...

❝ 2. Option: Use AUC(0-48)

I suppose you would do that for both treatments. In a way you would introduce a bias by using an under-estimated AUC... And you might be suspected again of playing with the data.

❝ 3. Option: Extrapolate to 72h (C(calc.)=5.69 using log-lin regression with * points) and calculate then AUC (result=595.85).

Introducing another bias. The question will be, how reliable is your estimate ? It will depend on the PK of the drug (mono- or multicompartmental), sampling times, etc. (Basically, if you remove the last sample, will the calculated half-life still be the terminal half-life ?). Probably closer to the truth than Option 2, but they may refer to the current EU guideline: "The exclusive use of compartmental based estimates are not recommended", and forget about "exclusive".

I'm not even sure my opinion would be worth twopence here, but... write in your protocol what you would do in such a situation, do it this way, and keep you fingers crossed, hoping for your file to be reviewed by an assessor with not more than 30 or 60 minutes on his hands (ElMaestro would say you have good chances).

Regards
Ohlbe

❝ 1. Option: Exclude subject

❝ 2. Option: Use AUC(0-48)

❝ 3. Option: Extrapolate to 72h (C(calc.)=5.69 using log-lin regression with * points) and calculate then AUC (result=595.85).

Hi,

I'd go for option 3 (after all we are used to extrapolations when it comes to AUCinf and nobody has a problem with that. If you can extrapolate something to inf then why not to 72 hrs. as well?!).

Excluding a subject is a possibility if something went wrong (vial broken, a UFO landed and the chromatograph melted, etc).
The CHMP has been working a lot on aspects of missing values etc, and they have come up with all sorts of strange concepts that have very little relevance for this situation.

Finally, depending on the combo of RMS and CMSs it might not make a difference at all what you choose. Of course, if you advertise in a very clear manner that something is fishy in the dataset then you might be able to force the assessor to look into it, but why not just leave it as it is and mention it on page 3848 and hope for the best.


Martin: 'Sensitivity analyses' (them being a lot of things) are probly a good idea. But it has absolutely no focus for PK assessors at the moment. But in a centralised procedure with survival curves the CHMP will sing with loud and clear voice "oh yeah, gimme gimme gimme sensitivity analyses"


EM.

Dear all!
Sorry for reviving the battered topic but for validation purposes I need to understand the methods of calculating partial areas in some nasty cases. I have a premonition that it would be hard to understand my question so I’ll try to use more illustrations…

Suppose we have to calculate AUC_0-72. The biggest problem is to decide: to extrapolate or nor to extrapolate. Let us follow the first scene. Suppose that the protocol states to use a simple linear trapezoid method to calculate AUC. How to calculate AUC_0-72 in the following situations?

1. There were time deviations in the first point (that is instead of t₀=0, we have, for example, t₀=1 hour)
   
2. There were time deviations in the last sample point (that is instead of t_last=72 h we have t_last=71 h or t_last=73 h). Additionally what if we have concentrations below LLOQ in the several last points (agree it is strange for drugs with long half-life but who knows..)?
   
3. There were abscent samples (NA) at the last time point 72 h

As Phoenix WinNonLin^® presents itself as a golden standard of NCA, I tried to understand what methods does it use in the uppermentioned cases.

To compare different methods I used the following concentration-time table:

time      Conc.
 ----------------------------------
0    0 (NA)
1   3
2   17
3   55
4   87
5   190
6   250
7   315
8   330
10   230
12   185
16   115
18   100
24   125
48   100
72(71,73)    77 (NA)
 ----------------------------------

1. Let us start with the first case: as it is intuitevily simple we just use a linear approximation to zero point. It is hard to invent an alternative approach because it is difficult to approximate by a known function the absorbtion part of the curve. Only if there was a non-zero concentration in the first sample (not enough wash-out or some unsufficient endogenous calculation) the results would differ.
AUC_last=AUC_all=AUC_0-72=8391

2. To calculate AUC_0-72 (AUC truncated) for the cases with t_last>72 h we can just truncate (cut down) at the time t=72 h (see the upper picture).
For t_last=73: AUC_last=AUC_all=8479.5; AUC_0-72=8402.0

But when we deal with t_last<72 h there appear different opportunities to get the value at t=72 h:
a). rude linear approximation (over the two last values or over the elimination period)
For t_last=71: C₇₂=76
b). log-linear interpolation (over the elimination period)
For t_last=71: C₇₂=76.84
( AUC_last=AUC_all=8302.5);
After assessing the concentration at 72 h we have to calculate the area under the last curve.
It can be done via:
- linear trapezoid method
(С₁+C₂)/2*(t₂-t₁)
AUC_0-72=8379.0
- log trapezoid method
(С₁-C₂)/(ln С₁-lnC₂)*(t₂-t₁)
AUC_0-72=8376.9
I can’t imagine what else there could be done. What method does WinNonLin use if it gets a value 8379.421 (very close to linear interpolation but not equal to it)

3. If there were no samples at t=72 h, the last point can be approximated by linear or log-linear interpolation and area can be calculated via linear or log trapezoid as in the previous case.
Comparing the results of the calculation I conclude that in this case WinNonLin use:
- Log-linear interpolation and log trapezoid method to calculate AUC_0-72.
AUC_last=AUC_all=6267; AUC_0-72=7983.3
The question arises: is it not strange to calculate the last part by log trapezoid method while the whole curve is calculated via untransformed trapezoid? Of course log interpolation is more preferable for the elimination part of the curve but we initially stated to use untransformed method.
Why does the situations 2) and 3) have different solution methods?