nobody
nothing

2017-05-23 11:07
(2501 d 12:31 ago)

Posting: # 17390
Views: 4,904
 

 More samples – less variability (for Cmax)? [Design Issues]

Hi again!

Lately I recognize a trend to increase number of samples in study designs for BE-studies to considerably more than 20 per application even for "simple" IR formulations.

First thought: $$$$ (CRO designs study :-) )

Second thought: Might there be a lower variability e.g. for Cmax with increased number of samples around Cmax (effect on AUC will be lower, in the absence of secondary peaks, I guess)? Gut feeling tells me: Possible. But to a relevant extent? Does increase in number of samples from about 16 (oldschool) to far beyond 20 really buy something regarding "quality" of data?

Isn't there an ethical/practical limit for blood sampling (from the top of my head I remember an absolute limit for blood volume to be taken within a trial...)?

Found some publications on the effect of sampling interval on outcome of BE-studies, but only limited systematic studies on number of samples, especially LSM (limited sampling models) appear to have been hip around year 2000.

Int J Clin Pharmacol Ther. 1999 Jun;37(6):275-81.
A limited sampling approach in bioequivalence studies: application to long half-life drugs and replicate design studies.
Mahmood I1, Mahayni H.

Biopharm Drug Dispos. 2001 Jul;22(5):179-90.
Evaluation of a limited sampling method used to determine the bioequivalence of highly variable drugs with long half-lives.
Jackson AJ

Any opinions/experience/feelings on that?

Kindest regards, nobody
Helmut
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Vienna, Austria,
2017-05-23 14:56
(2501 d 08:43 ago)

@ nobody
Posting: # 17393
Views: 4,385
 

 More samples – less variability (for Cmax)

Hi nobody,

❝ Lately I recognize a trend to increase number of samples in study designs for BE-studies to considerably more than 20 per application even for "simple" IR formulations.


❝ First thought: $$$$ (CRO designs study :-) )


Always correct but I think it’s more this one:

❝ Second thought: Might there be a lower variability e.g. for Cmax with increased number of samples around Cmax (effect on AUC will be lower, in the absence of secondary peaks, I guess)? Gut feeling tells me: Possible. But to a relevant extent? Does increase in number of samples from about 16 (oldschool) to far beyond 20 really buy something regarding "quality" of data?


Makes sense. See this oldie.

❝ Isn't there an ethical/practical limit for blood sampling (from the top of my head I remember an absolute limit for blood volume to be taken within a trial...)?


Yes there is. The total volume in the study should not exceed the one of a blood donation (if unavoidable, longer washout, measurement of HCT before later administrations, eventual exclusion of subjects…). But in the old days 10 mL / sample were taken and nowadays 5 mL are common. Still not an issue even for replicate designs. For really extensive sampling (i.e., gastric resistant formulations) 4-period replicate designs are problematic and 3-period replicates might be the only way out.

Since for the EMA AUC72 is acceptable for all IR products, in my studies I shift sampling towards the expected tmax since a reliable estimation of λz is no more needed.

Would be fun to simulate that. Makes a nice paper.

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Ohlbe
★★★

France,
2017-05-23 16:14
(2501 d 07:24 ago)

@ Helmut
Posting: # 17396
Views: 4,295
 

 Sample volume

Dear nobody and Helmut,

❝ ❝ Isn't there an ethical/practical limit for blood sampling (from the top of my head I remember an absolute limit for blood volume to be taken within a trial...)?


❝ Yes there is. The total volume in the study should not exceed the one of a blood donation (if unavoidable, longer washout, measurement of HCT before later administrations, eventual exclusion of subjects…). But in the old days 10 mL / sample were taken and nowadays 5 mL are common.


Agreed. And I think this volume could easily be further reduced. Many labs still develop methods starting with 500 µl of plasma, just like in the old days of HPLC/UV, even though they are now using LC-MS/MS which can easily achieve an LLOQ several orders of magnitude lower. It would be perfectly feasible in most cases to only use 100 µl of plasma and reduce the blood sampling volume to 3 ml. This would still leave more than enough for repeat analysis and ISR.

Regards
Ohlbe
nobody
nothing

2017-05-23 16:50
(2501 d 06:48 ago)

@ Ohlbe
Posting: # 17398
Views: 4,284
 

 Sample volume

❝ Agreed. And I think this volume could easily be further reduced. Many labs still develop methods starting with 500 µl of plasma, just like in the old days of HPLC/UV, even though they are now using LC-MS/MS which can easily achieve an LLOQ several orders of magnitude lower. It would be perfectly feasible in most cases to only use 100 µl of plasma and reduce the blood sampling volume to 3 ml. This would still leave more than enough for repeat analysis and ISR.


IIRC there are practical limitations WRT to obtaining plasma (size of Monvette, centrifugation, hemolysis, pipetting/storage of plasma?) so: not so easy to downsize in practice, I think. Might depend strongly on CRO, I guess...

Kindest regards, nobody
Ohlbe
★★★

France,
2017-05-23 21:00
(2501 d 02:38 ago)

@ nobody
Posting: # 17404
Views: 4,241
 

 Sample volume

Dear nobody,

❝ IIRC there are practical limitations WRT to obtaining plasma (size of Monvette, centrifugation, hemolysis, pipetting/storage of plasma?) so: not so easy to downsize in practice, I think.


3 ml vacutainers are commercially available with the usual anticoagulants (EDTA, Li heparin). No additional risk of hemolysis, AFAIK. Storage of plasma: I would definitively avoid 5 ml tubes... There are some very convenient smaller tubes with a screw cap and a conic bottom, already in common use at a number of places. It also saves space in freezers :-) which can compensate the additional cost of such tubes.

Regards
Ohlbe
nobody
nothing

2017-05-23 16:31
(2501 d 07:07 ago)

@ Helmut
Posting: # 17397
Views: 4,394
 

 More samples – less variability (for Cmax)

❝ Would be fun to simulate that. Makes a nice paper.


...same thought here, thought about reviving my old "S-plus" files with "retro-NONMEM" sim approach to study influence of analytical variability on parameters estimates in BE-trials :-) But no time for the next months.

Have a special compound here, as some percentage of volunteers simply end up with low exposure, apparently nobody (no, not me...) knows why. Would be the classical situation were more samples is only more $$$, no better data, or? ;-)

Kindest regards, nobody
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