selwa ts
☆

Algeria,
2021-10-31 10:13
(37 d 08:48 ago)

Posting: # 22663
Views: 554

planning of bioequivalence sampling [Bioanalytics]

Hello dear community, I am writing you in the hope to be guided me on the collecting blood program samples (sampling) from volunteers during a bioequivalence study,

1 / Are there any references to follow, or does it really depend on the nature of the molecule to be studied?

2 / Are there any precautions or recommendations to consider?

dshah
★

India/United Kingdom,
2021-11-01 10:34
(36 d 08:27 ago)

(edited by dshah on 2021-11-01 13:29)
@ selwa ts
Posting: # 22665
Views: 497

planning of bioequivalence sampling

Dear Selwa ts!
Generally you can get below conclusion from guidelines...
1. You need to capture absorption phase with on an average 3-4 time points. 1st time point should not be Cmax.
2. Capture the distribution phase by 3-4 time points.
3. Capture the elimination phase by 4-5 time points.

Study duration can be truncated to 72 hrs as per regulatory requirement or else the duration should be sufficient to capture the AUCt/AUC0-inf>0.8.

You can have different time points for fasting and fed study if they are studied separately.
The above requirement is minimum requirement and you can increase the time points if the blood loss is permissible by ethics committee.
You can consider that generally 16-24 time points are there in BE study.
As per FDA-"For most drugs we recommend that 12 to 18 samples, including a pre-dose sample, be collected per subject per dose. This sampling should continue for at least three or more terminal elimination half-lives of the drug to capture 90 percent of the relevant AUC."

Regards,
Dshah
ElMaestro
★★★

Denmark,
2021-11-07 19:47
(29 d 23:14 ago)

@ selwa ts
Posting: # 22668
Views: 332

Challenge - something for the programmers here

Hi all,

» 1 / Are there any references to follow, or does it really depend on the nature of the molecule to be studied?
»
» 2 / Are there any precautions or recommendations to consider?

One thing that occasionally crossed my mind was that I would love to see someone (no, I am of course not naming anyone and of course I do not have any particular person in mind, Helmut ) writing a function in R which takes some arguments of relevance and spits out a list of proposed sampling points.
Arguments might include anything known or anticipated about dose, half-life, lag time, expected Cmax, LLOQ, and so forth.
Obviously there could be a lot of ifs and buts and unknowns. But still something useful might be produced. Some arguments might be missing and then the function could highlight implied assumptions however wrong they might in reality be. Things like convenience could be factored in (for example, you don't want to wake of the volunteer at 4:30 am unless it is really necessary).

Here's a Valsartan SPC.
Here's a Valsartan PAR.
Let's just say I have an assay that I think has an LLOQ of 10 ng/mL or whatever, and let us ignore the fact that the PAR above lists suitable time points. I want to investigate BE for a 160 mg IR SODF.

Who can write a function that uses some of the info in the links above (or other links deemed relevant) and makes a reasonable proposal?

Pass or fail!
ElMaestro
Helmut
★★★

Vienna, Austria,
2021-11-07 23:33
(29 d 19:28 ago)

@ ElMaestro
Posting: # 22669
Views: 339

Really (really) tough stuff

Hi ElMaestro,

» One thing that occasionally crossed my mind was that I would love to see someone (no, I am of course not naming anyone and of course I do not have any particular person in mind, Helmut ) writing a function in R which takes some arguments of relevance and spits out a list of proposed sampling points. [etc., etc., …]

Fantastic idea!
In any software for PK modeling – with some efforts even in Base  nls() – you could obtain the VIF of the model based on different sampling schedules. Plot them for the primary parameters vs time. Around the extrema you find time points which are the most important ones. Others are luxury.
I did that for many years in WinNonlin and sometimes still today.
In the early 1990s I wanted to go even further. Given a guesstimate of the between-subject variability of $$\small{f}$$, $$\small{C_\textrm{max}}$$, and $$\small{k_\textrm{el}}$$ establish the goalposts of the bioanalytical method (LLOQ, ULOQ). Questions: Where to place the calibrators, how many calibrators + replicates are needed to give the most accurate/precise back-calculated concentrations? Tried a lot till I realized that bioanalytics is the least important part in this game.*

Dif-tor heh smusma 🖖
Helmut Schütz

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